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Sun Z, Wang Y, Liu S, Li H, He D, Xu H. Intestinal-region-specific functions of AHR in intrinsic enteric neurons during infections. Cell Rep 2025; 44:115524. [PMID: 40178975 DOI: 10.1016/j.celrep.2025.115524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/21/2025] [Accepted: 03/14/2025] [Indexed: 04/05/2025] Open
Abstract
Intrinsic enteric neurons (iENs) form a crucial neuronal network within the myenteric and submucosal plexus of the gastrointestinal tract, primarily responsible for regulating gut peristalsis. The mechanisms by which iENs sense and integrate dietary and microbial signals to regulate intestinal homeostasis and inflammation remain unclear. Here, we showed that environmental sensor aryl hydrocarbon receptor (AHR) was expressed in different iEN subsets in the ileum and colon and that AHR ligands differentially modulated iEN activity in these regions. Genetic perturbation of Ahr in neurons increased iEN activation in the ileum but, conversely, decreased it in the colon in response to different intestinal pathogens. Furthermore, neuronal AHR deficiency enhanced the clearance of bacterial pathogens, which was associated with increased proliferation and abundance of group 3 innate lymphoid cells in the ileum. Together, our findings demonstrate the region-specific functions of AHR in neurons in response to infections.
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Affiliation(s)
- Zijia Sun
- Fudan University, Shanghai 200433, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Yingsheng Wang
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Shaorui Liu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Hui Li
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Danyang He
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Heping Xu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; School of Life Sciences, Westlake University, Hangzhou 310024, China.
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Madison CA, Debler RA, Gallegos PL, Hillbrick L, Chapkin RS, Safe S, Eitan S. 1,4-dihydroxy-2-naphthoic acid prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced motor function deficits. Behav Pharmacol 2025; 36:40-46. [PMID: 39660867 PMCID: PMC11781791 DOI: 10.1097/fbp.0000000000000806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2024]
Abstract
Parkinson's disease (PD), characterized by death of dopaminergic neurons in the substantia nigra, is the second most prevalent progressive neurodegenerative disease. However, the etiology of PD is largely elusive. This study employed the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model to examine the effectiveness of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA), an aryl hydrocarbon receptor (AhR) active gut bacteria-derived metabolite, in mitigating MPTP's motoric deficits, and the role of AhR in mediating these effects. Male C57BL/6 mice were fed daily with vehicle, 20 mg/kg 1,4-DHNA, or AhR-inactive isomer 3,7-DHNA, for 3 weeks before administration of 80 mg/kg MPTP or vehicle. Four weeks later, mice were assessed for motoric functions. Both 1,4-DHNA and 3,7-DHNA prevented MPTP-induced deficits in the motor pole test and in the adhesive strip removal test. Additionally, 1,4-DHNA improved balance beam performance and completely prevented MPTP-induced reduction in stride length. In contrast, 3,7-DHNA, an AhR-inactive compound, did not improve balance beam performance and had only a partial effect on stride length. This study suggests that natural metabolites of gut microbiota, such as 1,4-DHNA, could be beneficial to counteract the development of motor deficits observed in PD. Thus, this study further supports the hypothesis that pathological and mitigating processes in the gut could play an essential role in PD development. Moreover, this indicates that 1,4-DHNA's ability to combat various motor deficits is likely mediated via multiple underlying molecular mechanisms. Specifically, AhR is involved, at least partially, in control of gait and bradykinesia, but it likely does not mediate the effects on fine motor skills.
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Affiliation(s)
- Caitlin A. Madison
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Roanna A. Debler
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Paula L. Gallegos
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Lauren Hillbrick
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Robert S. Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466 USA
| | - Shoshana Eitan
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
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Wei X, Sui K, Peng Y, Li S, Fang Y, Chen Z, Du X, Xie X, Tang H, Wen Q, Li J, He M, Cheng Q, Zhang W. Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Loaded Mir-29-3p Targets AhR to Improve Juvenile Idiopathic Arthritis via Inhibiting the Expression of IL-22 in CD4 + T Cell. Stem Cell Rev Rep 2025; 21:536-553. [PMID: 39621151 DOI: 10.1007/s12015-024-10827-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/03/2025]
Abstract
BACKGROUND Juvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory rheumatic diseases in children. Human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomes (HUCMSCs-Exos) are involved in autoimmune diseases. This study investigates the mechanism of HUCMSC-Exos in improving JIA by targeting AhR through delivery of miR-29-3p to inhibit IL-22 expression in CD4+ T cells. METHODS Collagen induced arthritis (CIA) mouse model was established, and mice were treated with HUCMSCs-Exos and miR-29-3p antagomir, respectively. CD4+ T cells from JIA patients were used for cell experiments. The mechanism was elucidated by histopathological staining, transmission electron microscopy (TEM), immunohistochemistry, CCK-8 assay, flow cytometry, Western blotting, real-time PCR, and enzyme-linked immunosorbent assay (ELISA), laser confocal microscopy, and luciferase assay. RESULT JIA-CD4+ T cells showed higher expression of IL-22 and lower the levels of miR-29-3p, while HUCMSCs-Exos significantly inhibited the expression of IL-22 and increased the levels of miR-29a-3p, miR-29b-3p, and miR-29c-3p in CD4+ T cells from JIA patients. The expression of miR-29a-3p, miR-29b-3p, miR-29c-3p, AhR, and IL-22 in CD4+ T cells was significantly reversed when co-cultured with HUCMSCs transfected with miR-29-3p mimic or miR-29-3p inhibitor. In vivo experiment, HUCMSCs-Exos ameliorated CIA mice by delivering miR-29-3p to inhibit AhR, IL-22, IL-22R1, MMP3, and MMP13 expression. Furthermore, HUCMSCs-Exos also deliver miR-29-3p targeting AhR expression to inhibit IL-22 in JIA-CD4 + T cells through alleviating arthritic synovial fibroblast activation. CONCLUSION HUCMSCs-Exos loaded miR-29-3p targets AhR to improve JIA via inhibiting the expression of IL-22 in CD4+ T cell, which provides a scientific basis for the treatment of JIA.
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Affiliation(s)
- Xinyi Wei
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Kunpeng Sui
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Yuanyuan Peng
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Sha Li
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Yu Fang
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Zhi Chen
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Xiao Du
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Xue Xie
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Haiming Tang
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - QiuYue Wen
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - JingWei Li
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Meilin He
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Qin Cheng
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Wei Zhang
- Pediatric Immunology and Rheumatology Department, School of Medicine, Chief Physician, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, No.1617, Riyue Avenue, Qingyang District, Chengdu, Sichuan, China.
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Ortega-Vallbona R, Palomino-Schätzlein M, Tolosa L, Benfenati E, Ecker GF, Gozalbes R, Serrano-Candelas E. Computational Strategies for Assessing Adverse Outcome Pathways: Hepatic Steatosis as a Case Study. Int J Mol Sci 2024; 25:11154. [PMID: 39456937 PMCID: PMC11508863 DOI: 10.3390/ijms252011154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
The evolving landscape of chemical risk assessment is increasingly focused on developing tiered, mechanistically driven approaches that avoid the use of animal experiments. In this context, adverse outcome pathways have gained importance for evaluating various types of chemical-induced toxicity. Using hepatic steatosis as a case study, this review explores the use of diverse computational techniques, such as structure-activity relationship models, quantitative structure-activity relationship models, read-across methods, omics data analysis, and structure-based approaches to fill data gaps within adverse outcome pathway networks. Emphasizing the regulatory acceptance of each technique, we examine how these methodologies can be integrated to provide a comprehensive understanding of chemical toxicity. This review highlights the transformative impact of in silico techniques in toxicology, proposing guidelines for their application in evidence gathering for developing and filling data gaps in adverse outcome pathway networks. These guidelines can be applied to other cases, advancing the field of toxicological risk assessment.
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Affiliation(s)
- Rita Ortega-Vallbona
- ProtoQSAR S.L., Calle Nicolás Copérnico 6, Parque Tecnológico de Valencia, 46980 Paterna, Spain; (R.O.-V.); (M.P.-S.); (R.G.)
| | - Martina Palomino-Schätzlein
- ProtoQSAR S.L., Calle Nicolás Copérnico 6, Parque Tecnológico de Valencia, 46980 Paterna, Spain; (R.O.-V.); (M.P.-S.); (R.G.)
| | - Laia Tolosa
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain;
- Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos, 28029 Madrid, Spain
| | - Emilio Benfenati
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy;
| | - Gerhard F. Ecker
- Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek Platz 2, 1090 Wien, Austria;
| | - Rafael Gozalbes
- ProtoQSAR S.L., Calle Nicolás Copérnico 6, Parque Tecnológico de Valencia, 46980 Paterna, Spain; (R.O.-V.); (M.P.-S.); (R.G.)
- MolDrug AI Systems S.L., Olimpia Arozena Torres 45, 46108 Valencia, Spain
| | - Eva Serrano-Candelas
- ProtoQSAR S.L., Calle Nicolás Copérnico 6, Parque Tecnológico de Valencia, 46980 Paterna, Spain; (R.O.-V.); (M.P.-S.); (R.G.)
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Oltramare C, Zennegg M, Graille M, Lerch S, Berthet A, Vernez D. Polychlorinated dibenzo- p-dioxin and dibenzofuran contamination of free-range eggs: estimation of the laying hen's soil ingestion based on a toxicokinetic model, and human consumption recommendations. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2024; 41:1302-1314. [PMID: 39133508 DOI: 10.1080/19440049.2024.2384416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 08/13/2024]
Abstract
Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) are ubiquitous in the environment. The main route of human exposure is through food consumption. Soil contamination can be problematic for sanitary safety depending on the usage of the soil, such as farming. In case of environmental soil contamination with PCDD/Fs, hen's eggs may be contaminated due to soil ingestion by hens. For this reason, it is important to understand the parameters that influence eggs' contamination when hens are raised in contaminated areas. After the discovery of a contaminated area in Lausanne (Switzerland), we collected hens' eggs from ten domestic-produced eggs and one farm. Based on PCDD/F measurements of eggs and soil, and a toxicokinetic model, we estimated individual hen's soil intake levels and highlighted appropriate parameters to predict the dose ingested. Recommended weekly consumption for home-produced eggs was calculated based on the tolerable weekly intake proposed by EFSA in 2018. The most important parameter to assess the soil ingestion does not seem to be the soil coverage by vegetation but rather the hen's pecking behaviour, the latter being difficult to estimate objectively. For this reason, we recommend using a realistic soil ingestion interval to assess the distribution of egg PCDD/F concentration from free-range hens reared on contaminated soil. The addition of soil contamination in the toxicokinetic model can then be used to recommend to the general population weekly consumption of eggs. The consumption by adults of free-range eggs produced on land with soil containing >90 ng toxic-equivalent (TEQ)/kg dry soil should be avoided. Even with a low level of soil contamination (1-5 ng TEQ/kg dry soil), we would recommend consuming not more than 5 eggs per week for adults and no more than 2 eggs for children below 4 years old.
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Affiliation(s)
- Christelle Oltramare
- Department of Occupational Health and Environment, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Epalinges, Switzerland
| | - Markus Zennegg
- EMPA, Laboratory for Advanced Analytical Technologies, Dübendorf, Switzerland
| | - Mélanie Graille
- Department of Occupational Health and Environment, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Epalinges, Switzerland
| | - Sylvain Lerch
- Ruminant Nutrition and Emissions, Agroscope, Posieux, Switzerland
| | - Aurélie Berthet
- Department of Occupational Health and Environment, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Epalinges, Switzerland
| | - David Vernez
- Department of Occupational Health and Environment, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Epalinges, Switzerland
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Rahmati M, Moghtaderi H, Mohammadi S, Al-Harrasi A. Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma: From immune modulation to therapeutic opportunities. World J Exp Med 2024; 14:96269. [PMID: 39312702 PMCID: PMC11372732 DOI: 10.5493/wjem.v14.i3.96269] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/26/2024] [Accepted: 06/14/2024] [Indexed: 08/29/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a substantial global health burden. Immune escape mechanisms are important in ESCC progression, enabling cancer cells to escape the surveillance of the host immune system. One key player in this process is the Aryl Hydrocarbon Receptor (AhR), which influences multiple cellular processes, including proliferation, differentiation, metabolism, and immune regulation. Dysregulated AhR signaling participates in ESCC development by stimulating carcinogenesis, epithelial-mesenchymal transition, and immune escape. Targeting AhR signaling is a potential therapeutic approach for ESCC, with AhR ligands showing efficacy in preclinical studies. Additionally, modification of AhR ligands and combination therapies present new opportunities for therapeutic intervention. This review aims to address the knowledge gap related to the role of AhR signaling in ESCC pathogenesis and immune escape.
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Affiliation(s)
- Mina Rahmati
- Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Tehran, Iran
| | - Hassan Moghtaderi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Ad Dakhiliyah, Oman
| | - Saeed Mohammadi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Ad Dakhiliyah, Oman
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Ad Dakhiliyah, Oman
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7
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Morgan SE, DeLouise LA. Assessing bioactivity of environmental water samples filtered using nanomembrane technology and mammalian cell lines. ECO-ENVIRONMENT & HEALTH 2024; 3:347-354. [PMID: 39281073 PMCID: PMC11400607 DOI: 10.1016/j.eehl.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 05/10/2024] [Accepted: 05/21/2024] [Indexed: 09/18/2024]
Abstract
This project reports on the use of a novel nanomembrane filtering technology to isolate and analyze the bioactivity of microplastic (MP)-containing debris from Lake Ontario water samples. Environmental MPs are a complex mixture of polymers and sorbed chemicals that are persistent and can exhibit a wide range of toxic effects. Since human exposure to MPs is unavoidable, it is necessary to characterize their bioactivity to assess potential health risks. This work seeks to quantify MP presence in the nearshore waters of Lake Ontario and begin to characterize the bioactivity of the filtrate containing MPs. We utilized silicon nitride (SiN) nanomembrane technology to isolate debris sized between 8 and 20 μm from lake water samples collected at various times and locations. MPs were identified with Nile red staining. Cell-based assays were conducted directly on the filtered debris to test for cell viability, aryl hydrocarbon receptor (AhR) activity, and interleukin 6 (IL-6) levels as a measure of proinflammatory response. All samples contained MPs. None of the isolated debris impacted cell viability. However, AhR activity and IL-6 levels varied over time. Additionally, no associations were observed between the amount of plastic and bioactivity. Observed differences in activity are likely due to variations in the physiochemical properties of debris between samples. Our results highlight the need for increased sampling to fully characterize the bioactivity of MPs in human cells and to elucidate the role that sample physiochemical and spatiotemporal properties play in this activity.
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Affiliation(s)
- Sarah E. Morgan
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Lake Ontario Center for Microplastics and Human Health in a Changing Environment, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Lisa A. DeLouise
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627, USA
- Department of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Lake Ontario Center for Microplastics and Human Health in a Changing Environment, University of Rochester Medical Center, Rochester, NY 14642, USA
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Coretti L, Buommino E, Lembo F. The aryl hydrocarbon receptor pathway: a linking bridge between the gut microbiome and neurodegenerative diseases. Front Cell Neurosci 2024; 18:1433747. [PMID: 39175504 PMCID: PMC11338779 DOI: 10.3389/fncel.2024.1433747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 07/31/2024] [Indexed: 08/24/2024] Open
Abstract
The Aryl hydrocarbon receptor (AHR) is a cytosolic receptor and ligand-activated transcription factor widely expressed across various cell types in the body. Its signaling is vital for host responses at barrier sites, regulating epithelial renewal, barrier integrity, and the activities of several types of immune cells. This makes AHR essential for various cellular responses during aging, especially those governing inflammation and immunity. In this review, we provided an overview of the mechanisms by which the AHR mediates inflammatory response at gut and brain level through signals from intestinal microbes. The age-related reduction of gut microbiota functions is perceived as a trigger of aberrant immune responses linking gut and brain inflammation to neurodegeneration. Thus, we explored gut microbiome impact on the nature and availability of AHR ligands and outcomes for several signaling pathways involved in neurodegenerative diseases and age-associated decline of brain functions, with an insight on Parkinson's and Alzheimer's diseases, the most common neurodegenerative diseases in the elderly. Specifically, we focused on microbial tryptophan catabolism responsible for the production of several AHR ligands. Perspectives for the development of microbiota-based interventions targeting AHR activity are presented for a healthy aging.
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Affiliation(s)
- Lorena Coretti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Task Force on Microbiome Studies, University of Naples Federico II, Naples, Italy
| | | | - Francesca Lembo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Task Force on Microbiome Studies, University of Naples Federico II, Naples, Italy
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Zhou S, Lei L, Jiang L, Fu C, Wen Y, Huang J, Zhang K, Huang J, Chen J, Zeng Q. Polycyclic aromatic hydrocarbons exposure associated with increased risk of psoriasis. Exp Dermatol 2024; 33:e15166. [PMID: 39171861 DOI: 10.1111/exd.15166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 08/06/2024] [Accepted: 08/11/2024] [Indexed: 08/23/2024]
Abstract
Psoriasis is considered to be multifactorial, with both genetic and environmental factors contributing to its development. Polycyclic aromatic hydrocarbons (PAHs) are widespread in the environment, originating from sources such as cigarette smoke, exhaust emissions, grilled foods, smoked foods and urban air. Researchs have established a link between PAHs exposure and autoimmune disorders; however, specific effects of PAHs on psoriasis remain underexplored. This study aims to evaluate the correlation between PAHs exposure and susceptibility to psoriasis. We analysed eight monohydroxy PAHs (1-Hydroxynaphthalene (1-NAP), 2-Hydroxynaphthalene (2-NAP), 3-Hydroxyfluorene (3-FLU), 2-Hydroxyfluorene (2-FLU), 1-Hydroxyphenanthrene (1-PHE), 1-Hydroxypyrene (1-PYR), 2-Hydroxyphenanthrene (2-PHE) and 3-Hydroxyphenanthrene (3-PHE)) in 5996 participants from the National Health and Nutrition Examination Survey (NHANES). We employed multivariate logistic regression, trend analysis, weighted quantile sum (WQS) regression and restricted cubic spline (RCS) analysis to investigate the relationship between PAHs exposure and psoriasis risk. Multivariate logistic regression and trend analysis revealed that monohydroxy PAHs, including 2-NAP, 3-FLU, 2-FLU and the mixture of 2-PHE and 3-PHE, are associated with an increased risk of psoriasis. Additionally, WQS regression showed a significant positive correlation between combined exposure to monohydroxy PAHs and psoriasis risk, with the mixture of 2-PHE and 3-PHE (47.3%) being the most influential factor. RCS regression further corroborated these findings. Specifically, 2-FLU can increase the expression of psoriasis-related inflammatory factors in HaCaT cells. In conclusion, PAHs exposure increases the risk of developing psoriasis. Efforts to reduce PAHs levels in the environment and minimise exposure are crucial for public health strategies aimed at preventing psoriasis.
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Affiliation(s)
- Shu Zhou
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Li Lei
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Ling Jiang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Chuhan Fu
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yaqing Wen
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Jiangfeng Huang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Keyi Zhang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Jinhua Huang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Jing Chen
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Qinghai Zeng
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
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10
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Koh YC, Pan MH. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS OMEGA 2024; 9:31298-31312. [PMID: 39072055 PMCID: PMC11270680 DOI: 10.1021/acsomega.4c04120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/19/2024] [Accepted: 06/26/2024] [Indexed: 07/30/2024]
Abstract
Circadian disruption has been found to increase the risk of metabolic diseases, brain disorders, and cancer. The aryl hydrocarbon receptor (AhR), responsible for xenobiotic metabolism, is known to be activated by certain environmental stimuli, including polycyclic aromatic hydrocarbons (PAHs). Exposure to these stimuli may lead to diseases related to circadian disruption, with AhR activation suggested as a leading cause. Both the aryl hydrocarbon receptor nuclear translocator (ARNT) and aryl hydrocarbon receptor nuclear translocator-like (BMAL1) are class II basic helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) proteins. These proteins form heterodimers with stimulated class I bHLH-PAS proteins, including circadian locomotor output cycles kaput (CLOCK) and AhR. Due to their sequential similarity, the overactivation of AhR by toxicants, such as PAHs, may lead to the formation of heterodimers with BMAL1, potentially causing circadian disruption. Dysregulation of BMAL1 can affect a wide range of metabolic genes, emphasizing its crucial roles. However, this issue has not been adequately addressed. Previous studies have reported that the inhibitory effects of phytochemicals on AhR activation can ameliorate diseases induced by environmental toxicants. Additionally, some phytochemicals have shown preventive effects on circadian misalignment. Therefore, this Review aims to explore potential strategies to prevent circadian disruption induced by food-borne toxicants, such as benzo[a]pyrene; to generate new ideas for future studies; and to highlight the importance of investigating these preventive strategies.
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Affiliation(s)
- Yen-Chun Koh
- Institute
of Food Science and Technology, National
Taiwan University, Taipei 106017, Taiwan
| | - Min-Hsiung Pan
- Institute
of Food Science and Technology, National
Taiwan University, Taipei 106017, Taiwan
- Department
of Medical Research, China Medical University Hospital, China Medical University, Taichung City 404327, Taiwan
- Department
of Health and Nutrition Biotechnology, Asia
University, Taichung City 413305, Taiwan
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11
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Singh G, Trehan S, Singh A, Goswami K, Farooq A, Antil P, Puri P, Bector G, Jain A, Azhar W. Aryl Hydrocarbon Receptor Signaling in Prostate Cancer Therapy: A Review of Implications for Anti-androgen Treatment Strategies and Resistance. Cureus 2024; 16:e65247. [PMID: 39184676 PMCID: PMC11342139 DOI: 10.7759/cureus.65247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
Prostate cancer is a leading cause of cancer-related morbidity and mortality in men, frequently exhibiting resistance to conventional anti-androgen therapies. This review investigates the emerging significance of the aryl hydrocarbon receptor (AhR) in prostate cancer, focusing on its role in modulating androgen receptor (AR) signaling and its potential as a therapeutic target. AhR, traditionally known for detoxifying harmful compounds, has been increasingly recognized for its dual capacity to either enhance or inhibit AR activity based on cellular context and specific coactivators. Furthermore, AhR influences tumor progression independently of AR by regulating genes involved in cell cycle control and apoptosis. This narrative review synthesizes current research on AhR's multifaceted roles in prostate cancer, evaluates its potential as a biomarker, and discusses the therapeutic implications of targeting AhR, particularly for hormone-refractory prostate cancer. Our findings underscore the necessity for personalized AhR-targeted therapies and advocate for continued clinical research to fully leverage AhR's therapeutic potential.
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Affiliation(s)
- Gurjot Singh
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Shubam Trehan
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Adarshpreet Singh
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Kanishka Goswami
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Amna Farooq
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Priya Antil
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Piyush Puri
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Gaurav Bector
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Aayush Jain
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Waqas Azhar
- Internal Medicine, Memorial Medical Center, Springfield, USA
- Internal Medicine, Saint John Hospital, Springfield, USA
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
- Hospital Medicine, Springfield Clinic, Springfield, USA
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12
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Debler RA, Gallegos PL, Ojeda AC, Perttula AM, Lucio A, Chapkin RS, Safe S, Eitan S. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces depression-like phenotype. Neurotoxicology 2024; 103:71-77. [PMID: 38838945 PMCID: PMC11288769 DOI: 10.1016/j.neuro.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 05/27/2024] [Accepted: 05/31/2024] [Indexed: 06/07/2024]
Abstract
The etiology of major depressive disorder (MDD) remains poorly understood. Our previous studies suggest a role for the aryl hydrocarbon receptor (AhR) in depression. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant, with a high AhR binding affinity, and an established benchmark for assessing AhR activity. Therefore, this study examined the effect of TCDD on depression-like behaviors. Female mice were fed standard chow or a high-fat diet (HFD) for 11 weeks, and their weight was recorded. Subsequently, they were tested for baseline sucrose preference and splash test grooming. Then, TCDD (0.1 µg/kg/day) or vehicle was administered orally for 28 days, and mice were examined for their sucrose preference and performances in the splash test, forced swim test (FST), and Morris water maze (MWM) task. TCDD significantly decreased sucrose preference, increased FST immobility time, and decreased groom time in chow-fed mice. HFD itself significantly reduced sucrose preference. However, TCDD significantly increased FST immobility time and decreased groom time in HFD-fed mice. A small decrease in bodyweight was observed only at the fourth week of daily TCDD administration in chow-fed mice, and no significant effects of TCDD on bodyweights were observed in HFD-fed mice. TCDD did not have a significant effect on spatial learning in the MWM. Thus, this study demonstrated that TCDD induces a depression-like state, and the effects were not due to gross lethal toxicity. This study further suggests that more studies should examine a possible role for AhR and AhR-active environmental pollutants in precipitating or worsening MDD.
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Affiliation(s)
- Roanna A Debler
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Paula L Gallegos
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Alexandra C Ojeda
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Andrea M Perttula
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Ashley Lucio
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
| | - Shoshana Eitan
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA.
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13
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Heine S, Alessandrini F, Grosch J, Graß C, Heldner A, Schnautz B, Grosch J, Buters J, Slusarenko BO, Krappmann D, Fallarino F, Ohnmacht C, Schmidt-Weber CB, Blank S. Activation of the aryl hydrocarbon receptor improves allergen-specific immunotherapy of murine allergic airway inflammation: a novel adjuvant option? Front Immunol 2024; 15:1397072. [PMID: 38915403 PMCID: PMC11194380 DOI: 10.3389/fimmu.2024.1397072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/29/2024] [Indexed: 06/26/2024] Open
Abstract
Background Allergen-specific immunotherapy (AIT) is able to restore immune tolerance to allergens in allergic patients. However, some patients do not or only poorly respond to current treatment protocols. Therefore, there is a need for deeper mechanistic insights and further improvement of treatment strategies. The relevance of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, has been investigated in several inflammatory diseases, including allergic asthma. However, its potential role in AIT still needs to be addressed. Methods A murine model of AIT in ovalbumin-induced allergic airway inflammation was performed in AhR-deficient (AhR-/-) and wild-type mice. Furthermore, AIT was combined with the application of the high-affinity AhR agonist 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ) as an adjuvant to investigate the effects of AhR activation on therapeutic outcome. Results Although AhR-/- mice suffer stronger allergic responses than wild-type mice, experimental AIT is comparably effective in both. Nevertheless, combining AIT with the administration of 10-Cl-BBQ improved therapeutic effects by an AhR-dependent mechanism, resulting in decreased cell counts in the bronchoalveolar fluid, decreased pulmonary Th2 and Th17 cell levels, and lower sIgE levels. Conclusion This study demonstrates that the success of AIT is not dependent on the AhR. However, targeting the AhR during AIT can help to dampen inflammation and improve tolerogenic vaccination. Therefore, AhR ligands might represent promising candidates as immunomodulators to enhance the efficacy of AIT.
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Affiliation(s)
- Sonja Heine
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Francesca Alessandrini
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Johannes Grosch
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Carina Graß
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets and Therapeutic Center, Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Alexander Heldner
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Benjamin Schnautz
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Johanna Grosch
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Jeroen Buters
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Benjamin O. Slusarenko
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Daniel Krappmann
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets and Therapeutic Center, Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | | | - Caspar Ohnmacht
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Carsten B. Schmidt-Weber
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
| | - Simon Blank
- Center of Allergy and Environment (ZAUM), Technical University of Munich, School of Medicine and Health & Helmholtz Munich, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Member of the Immunology and Inflammation Initiative of the Helmholtz Association, Munich, Germany
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14
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Mosa FES, AlRawashdeh S, El-Kadi AOS, Barakat K. Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations. J Chem Inf Model 2024; 64:2021-2034. [PMID: 38457778 DOI: 10.1021/acs.jcim.4c00169] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates biological signals to control various complicated cellular functions. It plays a crucial role in environmental sensing and xenobiotic metabolism. Dysregulation of AhR is associated with health concerns, including cancer and immune system disorders. Upon binding to AhR ligands, AhR, along with heat shock protein 90 and other partner proteins undergoes a transformation in the nucleus, heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological functions by inducing the transcription of various AhR-responsive genes. In this manuscript, the 3-dimensional structure of the entire human AhR is obtained using an artificial intelligence tool, and molecular dynamics (MD) simulations are performed to study different structural conformations. These conformations provide insights into the protein's function and movement in response to ligand binding. Understanding the dynamic behavior of AhR will contribute to the development of targeted therapies for associated health conditions. Therefore, we employ well-tempered metadynamics (WTE-metaD) simulations to explore the conformational landscape of AhR and obtain a better understanding of its functional behavior. Our computational results are in excellent agreement with previous experimental findings, revealing the closed and open states of helix α1 in the basic helix-loop-helix (bHLH domain) in the cytoplasm at the atomic level. We also predict the inactive form of AhR and identify Arginine 42 as a key residue that regulates switching between closed and open conformations in existing AhR modulators.
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Affiliation(s)
- Farag E S Mosa
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Sara AlRawashdeh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Khaled Barakat
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
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15
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Martin JC, da Silva Fernandes T, Chaudhry KA, Oshi M, Abrams SI, Takabe K, Rosario SR, Bianchi-Smiraglia A. Aryl hydrocarbon receptor suppresses STING-mediated type I IFN expression in triple-negative breast cancer. Sci Rep 2024; 14:5731. [PMID: 38459088 PMCID: PMC10923803 DOI: 10.1038/s41598-024-54732-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 02/15/2024] [Indexed: 03/10/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited, and rapid recurrence with distant metastases remains a significant challenge. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that, in TNBC systems, the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of STImulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate that the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy.
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Affiliation(s)
- Jeffrey C Martin
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | - Kanita A Chaudhry
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Masanori Oshi
- Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Scott I Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kazuaki Takabe
- Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Spencer R Rosario
- Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Anna Bianchi-Smiraglia
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
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16
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Kalinina TS, Kononchuk VV, Valembakhov IS, Pustylnyak VO, Kozlov VV, Gulyaeva LF. Expression of AhR-regulated miRNAs in non-small cell lung cancer in smokers and never smokers. BIOMEDITSINSKAIA KHIMIIA 2024; 70:52-60. [PMID: 38450681 DOI: 10.18097/pbmc20247001052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2024]
Abstract
Smoking is a risk factor for non-small cell lung cancer (NSCLC). The most common subtypes of NSCLC are lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). The cigarette smoke contains aryl hydrocarbon receptor (AhR) ligands, such as benzo(a)pyrene (BaP). By activating the AhR, BaP can change the expression of many genes, including miRNA-encoding genes. In this study, we have evaluated the expression of few miRNAs potentially regulated by AhR (miR-21, -342, -93, -181a, -146a), as well as CYP1A1, a known AhR target gene, in lung tumor samples from smoking (n=40) and non-smoking (n=30) patients with LAC and from smoking patients with SCC (n=40). We have also collected macroscopically normal lung tissue >5 cm from the tumor margin. We compared the obtained data on the miRNA expression in tumors with data from The Cancer Genome Atlas (TCGA). We found that in 76.7% of non-smoking LAC patients, CYP1A1 mRNA was not detected in tumor and normal lung tissues, while in smoking patients, CYP1A1 expression was detected in tumors in almost half of the cases (47.5% for SCC and 42.5% for LAC). The expression profile of AhR-regulated miRNAs differed between LAC and SCC and depended on the smoking status. In LAC patients, the expression of oncogenic miRNA-21 and miRNA-93 in tumors was higher than in normal lung tissue from the same patients. However, in SCC patients from our sample, the levels of these miRNAs in tumor and non-transformed lung tissue did not differ significantly. The results of our studies and TCGA data indicate that the expression levels of miRNA-181a and miRNA-146a in LAC are associated with smoking: expression of these miRNAs was significantly lower in tumors of smokers. It is possible that their expression is regulated by AhR and AhRR (AhR repressor), and inhibition of AhR by AhRR leads to a decrease in miRNA expression in tumors of smoking patients. Overall, these results confirm that smoking has an effect on the miRNA expression profile. This should be taken into account when searching for new diagnostic and therapeutic targets for NSCLC.
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Affiliation(s)
- T S Kalinina
- Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia
| | - V V Kononchuk
- Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia; Meshalkin National Medical Research Center, Ministry of Health of the Russian Federation, Novosibirsk, Russia
| | - I S Valembakhov
- Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia
| | - V O Pustylnyak
- Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia; Novosibirsk State University, Novosibirsk, Russia
| | - V V Kozlov
- Novosibirsk Regional Oncological Dispensary, Novosibirsk, Russia
| | - L F Gulyaeva
- Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia
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17
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Beurel E. Stress in the microbiome-immune crosstalk. Gut Microbes 2024; 16:2327409. [PMID: 38488630 PMCID: PMC10950285 DOI: 10.1080/19490976.2024.2327409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/04/2024] [Indexed: 03/19/2024] Open
Abstract
The gut microbiota exerts a mutualistic interaction with the host in a fragile ecosystem and the host intestinal, neural, and immune cells. Perturbations of the gastrointestinal track composition after stress have profound consequences on the central nervous system and the immune system. Reciprocally, brain signals after stress affect the gut microbiota highlighting the bidirectional communication between the brain and the gut. Here, we focus on the potential role of inflammation in mediating stress-induced gut-brain changes and discuss the impact of several immune cells and inflammatory molecules of the gut-brain dialogue after stress. Understanding the impact of microbial changes on the immune system after stress might provide new avenues for therapy.
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Affiliation(s)
- Eléonore Beurel
- Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
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18
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Zhou F, He K, Cai JJ, Davidson LA, Chapkin RS, Ni Y. A Unified Bayesian Framework for Bi-overlapping-Clustering Multi-omics Data via Sparse Matrix Factorization. STATISTICS IN BIOSCIENCES 2023; 15:669-691. [PMID: 38179127 PMCID: PMC10766378 DOI: 10.1007/s12561-022-09350-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 04/10/2021] [Accepted: 06/06/2022] [Indexed: 11/27/2022]
Abstract
The advances of modern sequencing techniques have generated an unprecedented amount of multi-omics data which provide great opportunities to quantitatively explore functional genomes from different but complementary perspectives. However, distinct modalities/sequencing technologies generate diverse types of data which greatly complicate statistical modeling because uniquely optimized methods are required for handling each type of data. In this paper, we propose a unified framework for Bayesian nonparametric matrix factorization that infers overlapping bi-clusters for multi-omics data. The proposed method adaptively discretizes different types of observations into common latent states on which cluster structures are built hierarchically. The proposed Bayesian nonparametric method is able to automatically determine the number of clusters. We demonstrate the utility of the proposed method using simulation studies and applications to a single-cell RNA-sequencing dataset, a combination of single-cell RNA-sequencing and single-cell ATAC-sequencing dataset, a bulk RNA-sequencing dataset, and a DNA methylation dataset which reveal several interesting findings that are consistent with biological literature.
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Affiliation(s)
- Fangting Zhou
- Institute of Statistics and Big Data, Renmin University of China, Beijing, China
- Department of Statistics, Texas A&M University, College Station, USA
| | - Kejun He
- Institute of Statistics and Big Data, Renmin University of China, Beijing, China
| | - James J. Cai
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, USA
| | - Laurie A. Davidson
- Department of Nutrition and Food Science, Texas A&M University, College Station, USA
- Program in Integrative Nutrition and Complex Diseases, Texas A &M University, College Station, USA
| | - Robert S. Chapkin
- Department of Nutrition and Food Science, Texas A&M University, College Station, USA
- Program in Integrative Nutrition and Complex Diseases, Texas A &M University, College Station, USA
| | - Yang Ni
- Department of Statistics, Texas A&M University, College Station, USA
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19
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Debler RA, Madison CA, Hillbrick L, Gallegos P, Safe S, Chapkin RS, Eitan S. Selective aryl hydrocarbon receptor modulators can act as antidepressants in obese female mice. J Affect Disord 2023; 333:409-419. [PMID: 37084978 PMCID: PMC10561895 DOI: 10.1016/j.jad.2023.04.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/27/2023] [Accepted: 04/14/2023] [Indexed: 04/23/2023]
Abstract
BACKGROUND Obese females are more likely to suffer from depression and are also more likely to be resistant to current medications. This study examined the potential antidepressant-like effects of 1,4-dihydroxy-2-napthoic acid (DHNA), a selective aryl hydrocarbon receptor modulator (SAhRM), in obese female mice. METHODS Obesity was established by feeding C57BL/6N female mice a high fat diet (HFD) for 9-10 weeks. Subsequently, mice were subjected to unpredictable chronic mild stress (UCMS) or remained unstressed. Daily administration of vehicle or 20 mg/kg DHNA began three weeks prior or on the third week of UCMS. Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash and tape groom tests), anxiety (open-field test, light/dark test, novelty-induced hypophagia), and cognition (object location recognition, novel object recognition, Morris water maze). RESULTS UCMS did not alter, and DHNA slightly increased, weight gain in HFD-fed females. HFD decreased sucrose preference, increased FST immobility time, but did not alter splash and tape tests' grooming time. UCMS did not have additional effects on sucrose preference. UCMS further increased FST immobility time and decreased splash and tape tests' grooming time; these effects were prevented and reversed by DHNA treatment. HFD did not affect behaviors in the cognitive tests. UCMS impaired spatial learning; this effect was not prevented nor reversed by DHNA. CONCLUSIONS DHNA protected against UCMS-induced depression-like behaviors in HFD-fed female mice. DHNA neither improved nor worsened UCMS-induced impairment of spatial learning. Our findings indicate that DHNA has high potential to act as an antidepressant in obese females.
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Affiliation(s)
- Roanna A Debler
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Caitlin A Madison
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Lauren Hillbrick
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Paula Gallegos
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Shoshana Eitan
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA.
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20
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Grishanova AY, Klyushova LS, Perepechaeva ML. AhR and Wnt/β-Catenin Signaling Pathways and Their Interplay. Curr Issues Mol Biol 2023; 45:3848-3876. [PMID: 37232717 DOI: 10.3390/cimb45050248] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/27/2023] Open
Abstract
As evolutionarily conserved signaling cascades, AhR and Wnt signaling pathways play a critical role in the control over numerous vital embryonic and somatic processes. AhR performs many endogenous functions by integrating its signaling pathway into organ homeostasis and into the maintenance of crucial cellular functions and biological processes. The Wnt signaling pathway regulates cell proliferation, differentiation, and many other phenomena, and this regulation is important for embryonic development and the dynamic balance of adult tissues. AhR and Wnt are the main signaling pathways participating in the control of cell fate and function. They occupy a central position in a variety of processes linked with development and various pathological conditions. Given the importance of these two signaling cascades, it would be interesting to elucidate the biological implications of their interaction. Functional connections between AhR and Wnt signals take place in cases of crosstalk or interplay, about which quite a lot of information has been accumulated in recent years. This review is focused on recent studies about the mutual interactions of key mediators of AhR and Wnt/β-catenin signaling pathways and on the assessment of the complexity of the crosstalk between the AhR signaling cascade and the canonical Wnt pathway.
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Affiliation(s)
- Alevtina Y Grishanova
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, Novosibirsk 630117, Russia
| | - Lyubov S Klyushova
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, Novosibirsk 630117, Russia
| | - Maria L Perepechaeva
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, Novosibirsk 630117, Russia
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21
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Saranya GR, Viswanathan P. Gut microbiota dysbiosis in AKI to CKD transition. Biomed Pharmacother 2023; 161:114447. [PMID: 37002571 DOI: 10.1016/j.biopha.2023.114447] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND AND AIM The symptoms of acute kidney injury (AKI) include a sudden drop-in glomerular filtration rate (GFR), a rise in serum creatinine (sCr), blood urea nitrogen (BUN), and electrolytes, which leads to a rapid loss of kidney function. Chronic kidney disease progresses when AKI symptoms persist for over three months or 90 days. Numerous prevalent secondary risk factors, including diabetes, hypertension, obesity, and heart illness, are directly or indirectly linked to the development of AKI and the switch from AKI to CKD. Recently, the change of intestinal bacteria known as "gut dysbiosis" has been linked to distant organ dysfunction, including the heart, lungs, kidneys, and brain. Indirectly or directly, gut dysbiosis contributes to the progression of CKD and AKI. However, the effects of gut dysbiosis and the mechanism of action in the progression from AKI to CKD are unknown or need further investigation. The mechanism by which gut dysbiosis initiates AKI's progression to CKD should be explicitly concerned. The review primarily focuses on the action of gut dysbiosis in kidney disease, the effects of dysbiosis, the characterisation of dysbiosis and its pathogenic products, the various pathogenic routes and mechanism involved in expediting the transition from AKI to CKD. CONCLUSION We identified and briefly reviewed the impacts of dysbiosis in various situations such as hypoxia, mitochondrial induced reactive oxygen species (mtROS), aryl hydrocarbon receptor (AhR) activation and microbiota derived uremic toxemic substances profoundly to push AKI to CKD conditions.
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Affiliation(s)
- G R Saranya
- Renal Research Lab, School of Bio Sciences and Technology, Pearl Research Park, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
| | - Pragasam Viswanathan
- Renal Research Lab, School of Bio Sciences and Technology, Pearl Research Park, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India.
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22
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Sadeghi Shermeh A, Royzman D, Kuhnt C, Draßner C, Stich L, Steinkasserer A, Knippertz I, Wild AB. Differential Modulation of Dendritic Cell Biology by Endogenous and Exogenous Aryl Hydrocarbon Receptor Ligands. Int J Mol Sci 2023; 24:ijms24097801. [PMID: 37175508 PMCID: PMC10177790 DOI: 10.3390/ijms24097801] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/17/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a decisive regulatory ligand-dependent transcription factor. It binds highly diverse ligands, which can be categorized as either endogenous or exogenous. Ligand binding activates AhR, which can adjust inflammatory responses by modulating immune cells such as dendritic cells (DCs). However, how different AhR ligand classes impact the phenotype and function of human monocyte-derived DCs (hMoDCs) has not been extensively studied in a comparative manner. We, therefore, tested the effect of the representative compounds Benzo(a)pyrene (BP), 6-formylindolo[3,2-b]carbazole (FICZ), and Indoxyl 3-sulfate (I3S) on DC biology. Thereby, we reveal that BP significantly induces a tolerogenic response in lipopolysaccharide-matured DCs, which is not apparent to the same extent when using FICZ or I3S. While all three ligand classes activate AhR-dependent pathways, BP especially induces the expression of negative immune regulators, and subsequently strongly subverts the T cell stimulatory capacity of DCs. Using the CRISPR/Cas9 strategy we also prove that the regulatory effect of BP is strictly AhR-dependent. These findings imply that AhR ligands contribute differently to DC responses and incite further studies to uncover the mechanisms and molecules which are involved in the induction of different phenotypes and functions in DCs upon AhR activation.
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Affiliation(s)
- Atefeh Sadeghi Shermeh
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Christine Kuhnt
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Christina Draßner
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Ilka Knippertz
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Andreas B Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
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23
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Madison CA, Hillbrick L, Kuempel J, Albrecht GL, Landrock KK, Safe S, Chapkin RS, Eitan S. Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms. Behav Brain Res 2023; 440:114256. [PMID: 36528169 PMCID: PMC9839636 DOI: 10.1016/j.bbr.2022.114256] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/03/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is a key regulator in the microbiome-gut-brain axis, and AhR-active microbial metabolites modulate multiple neuronal responses. We recently demonstrated that 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (DHNA), two selective AhR modulators (SAhRMs), act as antidepressants in female mice. Thus, to examine the role of intestinal AhR in depression, anxiety, and spatial learning, this study employed transgenic mice in which the AhR was knockout only in the intestinal epithelium (AhRΔIEC). Additionally, this study examined whether the antidepressant effects of dietary DIM and DHNA is mediated by intestinal AhR. AhRΔIEC and WT female mice were fed daily with vehicle, 20 mg/kg DIM or DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for weight gain, anhedonia-like behavior (sucrose preference test), anxiety levels (open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests), and spatial learning (Morris water maze). UCMS reduced weight gain in AhRΔIECs, but not WTs. Moreover, UCMS initially reduced sucrose preference in both AhRΔIECs and WTs, but over 4 weeks of UCMS, AhRΔIECs develop resilience to UCMS-induced anhedonia. Additionally, AhRΔIECs exhibit slightly reduced anxiety in certain tests and faster spatial learning. DIM and DHNA acted as antidepressants in both AhRΔIECs and WTs. Thus, this study suggests that intestinal AhR plays differential roles, mitigating stress effects on weight gain, and increasing stress effects on mood. However, the site of antidepressant action of SAhRMs, such as DIM and DHNA, is not dependent on the expression of intestinal AhR.
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Affiliation(s)
- Caitlin A Madison
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Lauren Hillbrick
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Jacob Kuempel
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Georgia Lee Albrecht
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA
| | - Kerstin K Landrock
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Shoshana Eitan
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, 4235 TAMU, College Station, TX 77843, USA.
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24
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Mao ZH, Gao ZX, Liu DW, Liu ZS, Wu P. Gut microbiota and its metabolites - molecular mechanisms and management strategies in diabetic kidney disease. Front Immunol 2023; 14:1124704. [PMID: 36742307 PMCID: PMC9896007 DOI: 10.3389/fimmu.2023.1124704] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 01/06/2023] [Indexed: 01/22/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus and is also one of the serious risk factors in cardiovascular events, end-stage renal disease, and mortality. DKD is associated with the diversified, compositional, and functional alterations of gut microbiota. The interaction between gut microbiota and host is mainly achieved through metabolites, which are small molecules produced by microbial metabolism from exogenous dietary substrates and endogenous host compounds. The gut microbiota plays a critical role in the pathogenesis of DKD by producing multitudinous metabolites. Nevertheless, detailed mechanisms of gut microbiota and its metabolites involved in the occurrence and development of DKD have not been completely elucidated. This review summarizes the specific classes of gut microbiota-derived metabolites, aims to explore the molecular mechanisms of gut microbiota in DKD pathophysiology and progression, recognizes biomarkers for the screening, diagnosis, and prognosis of DKD, as well as provides novel therapeutic strategies for DKD.
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Affiliation(s)
- Zi-Hui Mao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Institute of Nephrology, Zhengzhou University, Zhengzhou, China,Henan Province Research Center for Kidney Disease, Zhengzhou, China,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhong-Xiuzi Gao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Institute of Nephrology, Zhengzhou University, Zhengzhou, China,Henan Province Research Center for Kidney Disease, Zhengzhou, China,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Dong-Wei Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Institute of Nephrology, Zhengzhou University, Zhengzhou, China,Henan Province Research Center for Kidney Disease, Zhengzhou, China,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhang-Suo Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Institute of Nephrology, Zhengzhou University, Zhengzhou, China,Henan Province Research Center for Kidney Disease, Zhengzhou, China,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China,*Correspondence: Peng Wu, ; Zhang-Suo Liu,
| | - Peng Wu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Institute of Nephrology, Zhengzhou University, Zhengzhou, China,Henan Province Research Center for Kidney Disease, Zhengzhou, China,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China,*Correspondence: Peng Wu, ; Zhang-Suo Liu,
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25
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Vernez D, Oltramare C, Sauvaget B, Demougeot-Renard H, Aicher L, Roth N, Rossi I, Radaelli A, Lerch S, Marolf V, Berthet A. Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) soil contamination in Lausanne, Switzerland: Combining pollution mapping and human exposure assessment for targeted risk management. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 316:120441. [PMID: 36349640 DOI: 10.1016/j.envpol.2022.120441] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 06/16/2023]
Abstract
In December 2020, high soil concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were discovered across large parts of Lausanne, Switzerland. Concentrations reached up to 640 ng TEQWHO-2005/kg dry weight. The most likely source was a former municipal waste incinerator. A three-step, multidisciplinary approach to human health risk assessment was conducted to determine the potential population exposure to PCDD/Fs and identify appropriate preventive measures. First, exposure scenarios were developed based on contaminated land uses. Second, the toxicological risks of different scenarios were evaluated using a toxicokinetic model estimating increases in blood serum PCDD/F concentrations over background concentrations from the general population's food consumption. Third, a detailed geostatistical mapping of PCDD/F soil contamination was performed. Stochastic simulations with an external drift and an anisotropic model of the variogram were generated to incorporate the effects of distance from emission source, topography, and main wind directions on the spatial distribution of PCDD/Fs in topsoil. Three main scenarios were assessed: i) direct ingestion of soil by children in playgrounds; ii) consumption of vegetables from private gardens by children and adults; and iii) consumption of food from livestock and poultry raised on contaminated soil. The worst exposure scenario involved the consumption of eggs from private hen houses, resulting in PCDD/F concentrations in serum an order of magnitude higher than might normally be expected. No relevant increases in serum concentrations were calculated for direct soil ingestion and vegetable consumption, except for cucurbitaceous vegetables. Combining mapping and exposure scenario assessment resulted in targeted protective measures for land users, especially concerning food consumption. The results also raised concerns about the potential unsafe consumption of products derived from animals raised on land with PCDD/F concentrations only moderately over environmental background levels.
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Affiliation(s)
- David Vernez
- Department of Occupational and Environmental Health, Center for Primary Care and Public Health (Unisanté), University of Lausanne, CH-1066 Epalinges, Switzerland.
| | - Christelle Oltramare
- Department of Occupational and Environmental Health, Center for Primary Care and Public Health (Unisanté), University of Lausanne, CH-1066 Epalinges, Switzerland
| | | | | | - Lothar Aicher
- Swiss Centre for Applied Human Toxicology (SCAHT) and Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland
| | - Nicolas Roth
- Swiss Centre for Applied Human Toxicology (SCAHT) and Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland
| | - Isabelle Rossi
- Department of Occupational and Environmental Health, Center for Primary Care and Public Health (Unisanté), University of Lausanne, CH-1066 Epalinges, Switzerland
| | - Arianna Radaelli
- Public Health Service, Canton of Vaud, CH-1014 Lausanne, Switzerland
| | - Sylvain Lerch
- Ruminant Research Group, Agroscope, CH-1725 Posieux, Switzerland
| | | | - Aurélie Berthet
- Department of Occupational and Environmental Health, Center for Primary Care and Public Health (Unisanté), University of Lausanne, CH-1066 Epalinges, Switzerland
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26
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Khazaal AQ, Haque N, Krager CR, Krager SL, Chambers C, Wilber A, Tischkau SA. Aryl hydrocarbon receptor affects circadian-regulated lipolysis through an E-Box-dependent mechanism. Mol Cell Endocrinol 2023; 559:111809. [PMID: 36283500 PMCID: PMC10509633 DOI: 10.1016/j.mce.2022.111809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
An internal circadian clock regulates timing of systemic energy homeostasis. The central clock in the hypothalamic suprachiasmatic nucleus (SCN) directs local clocks in peripheral tissues such as liver, muscle, and adipose tissue to synchronize metabolism with food intake and rest/activity cycles. Aryl hydrocarbon receptor (AhR) interacts with the molecular circadian clockworks. Activation of AhR dampens rhythmic expression of core clock genes, which may lead to metabolic dysfunction. Given the importance of appropriately-timed adipose tissue function to regulation of energy homeostasis, this study focused on mechanisms by which AhR may influence clock-controlled adipose tissue activity. We hypothesized that AhR activation in adipose tissue would impair lipolysis by dampening adipose rhythms, leading to a decreased lipolysis rate during fasting, and subsequently, altered serum glucose concentrations. Levels of clock gene and lipolysis gene transcripts in mouse mesenchymal stem cells (BMSCs) differentiated into mature adipocytes were suppressed by the AhR agonist β-napthoflavone (BNF), in an AhR dependent manner. BNF altered rhythms of core clock gene and lipolysis gene transcripts in C57bl6/J mice. BNF reduced serum free fatty acids, glycerol and liver glycogen. Chromatin immunoprecipitation indicated that BNF increased binding of AhR to E-Box elements in clock gene and lipolysis gene promoters. These data establish a link between AhR activation and impaired lipolysis, specifically by altering adipose tissue rhythmicity. In response to the decreased available energy from impaired lipolysis, the body increases glycogenolysis, thereby degrading more glycogen to provide necessary energy.
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Affiliation(s)
- Ali Qasim Khazaal
- Biotechnology Department, College of Science, University of Baghdad, Baghdad, Iraq; Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Nazmul Haque
- Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Callie R Krager
- Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Stacey L Krager
- Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Christopher Chambers
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Andrew Wilber
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Shelley A Tischkau
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA; Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA.
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27
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Madison CA, Debler RA, Vardeleon NI, Hillbrick L, Jayaraman A, Safe S, Chapkin RS, Eitan S. Sex-dependent differences in the stress mitigating and antidepressant effects of selective aryl hydrocarbon receptor modulators. J Affect Disord 2022; 319:213-220. [PMID: 36206882 PMCID: PMC10391660 DOI: 10.1016/j.jad.2022.09.155] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/25/2022] [Accepted: 09/30/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Our recent study demonstrated that selective aryl hydrocarbon receptor modulators (SAhRMs), such as 1,4-dihydroxy-2-napthoic acid (DHNA) act as antidepressants in female mice. Given that some effects of certain SAhRMs are known to also be mediated via estrogen receptor signaling, this study examined whether the effects of SAhRMs on mood, emotional state, and cognition are sex-dependent. METHODS C57BL/6N mice were fed with vehicle or 20 mg/kg DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash test, tape groom test), emotional state (open-field test, light/dark test, marble burying, novelty-induced hypophagia, elevated-plus maze), and cognition (object location recognition, novel object recognition, Morris water maze). RESULTS In females, UCMS decreased sucrose preference and increased FST immobility time; both effects were prevented by DHNA. In males, UCMS increased FST immobility time, and increased the latency to groom in the splash test. These effects were not mitigated by DHNA. However, in males, UCMS induced an increase in novelty-induced locomotion, an increase in the time spent in the light compartment in the L/D test, and an increase in the time spent with an object in a novel location. These effects were prevented by DHNA. CONCLUSIONS Our findings indicate that DHNA has high potential to act as antidepressants in females. However, given classical interpretation, DHNA did not appear to act as an antidepressant in males. Nonetheless, our findings indicate that DHNA can mitigate stress effects and reactivity in males.
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Affiliation(s)
- Caitlin A Madison
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Roanna A Debler
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Nathan I Vardeleon
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Lauren Hillbrick
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Shoshana Eitan
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA.
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28
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Safe S, Zhang L. The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer. Cancers (Basel) 2022; 14:5574. [PMID: 36428667 PMCID: PMC9688153 DOI: 10.3390/cancers14225574] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/27/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Breast cancer is a complex disease which is defined by numerous cellular and molecular markers that can be used to develop more targeted and successful therapies. The aryl hydrocarbon receptor (AhR) is overexpressed in many breast tumor sub-types, including estrogen receptor -positive (ER+) tumors; however, the prognostic value of the AhR for breast cancer patient survival is not consistent between studies. Moreover, the functional role of the AhR in various breast cancer cell lines is also variable and exhibits both tumor promoter- and tumor suppressor- like activity and the AhR is expressed in both ER-positive and ER-negative cells/tumors. There is strong evidence demonstrating inhibitory AhR-Rα crosstalk where various AhR ligands induce ER degradation. It has also been reported that different structural classes of AhR ligands, including halogenated aromatics, polynuclear aromatics, synthetic drugs and other pharmaceuticals, health promoting phytochemical-derived natural products and endogenous AhR-active compounds inhibit one or more of breast cancer cell proliferation, survival, migration/invasion, and metastasis. AhR-dependent mechanisms for the inhibition of breast cancer by AhR agonists are variable and include the downregulation of multiple genes/gene products such as CXCR4, MMPs, CXCL12, SOX4 and the modulation of microRNA levels. Some AhR ligands, such as aminoflavone, have been investigated in clinical trials for their anticancer activity against breast cancer. In contrast, several publications have reported that AhR agonists and antagonists enhance and inhibit mammary carcinogenesis, respectively, and differences between the anticancer activities of AhR agonists in breast cancer may be due in part to cell context and ligand structure. However, there are reports showing that the same AhR ligand in the same breast cancer cell line gives opposite results. These differences need to be resolved in order to further develop and take advantage of promising agents that inhibit mammary carcinogenesis by targeting the AhR.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
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29
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Patil NY, Rus I, Downing E, Mandala A, Friedman JE, Joshi AD. Cinnabarinic Acid Provides Hepatoprotection Against Nonalcoholic Fatty Liver Disease. J Pharmacol Exp Ther 2022; 383:32-43. [PMID: 35933113 PMCID: PMC9513857 DOI: 10.1124/jpet.122.001301] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/12/2022] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic condition in which excess lipids accumulate in the liver and can lead to a range of progressive liver disorders including non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. While lifestyle and diet modifications have proven to be effective as NAFLD treatments, they are not sustainable in the long-term, and currently no pharmacological therapies are approved to treat NAFLD. Our previous studies demonstrated that cinnabarinic acid (CA), a novel endogenous Aryl hydrocarbon Receptor (AhR) agonist, activates the AhR target gene, Stanniocalcin 2, and confers cytoprotection against a plethora of ER/oxidative stressors. In this study, the hepatoprotective and anti-steatotic properties of CA were examined against free fatty-acid-induced in vitro and high-fat-diet fed in vivo NAFLD models. The results demonstrated that CA treatment significantly lowered weight gain and attenuated hepatic lipotoxicity both before and after the established fatty liver, thereby protecting against steatosis, inflammation, and liver injury. CA mitigated intracellular free fatty acid uptake concomitant with the downregulation of CD36/fatty acid translocase. Genes involved in fatty acid and triglyceride synthesis were also downregulated in response to CA treatment. Additionally, suppressing AhR and Stc2 expression using RNA interference in vitro verified that the hepatoprotective effects of CA were absolutely dependent on both AhR and its target, Stc2. Collectively, our results demonstrate that the endogenous AhR agonist, CA, confers hepatoprotection against NAFLD by regulating hepatic fatty acid uptake and lipogenesis. SIGNIFICANCE STATEMENT: In this study using in vitro and in vivo models, we demonstrate that cinnabarinic acid (CA), an endogenous AhR agonist, provides protection against non-alcoholic fatty liver disease. CA bestows cytoprotection against steatosis and liver injury by controlling expression of several key genes associated with lipid metabolism pathways, limiting the hepatic lipid uptake, and controlling liver inflammation. Moreover, CA-induced hepatoprotection is absolutely dependent on AhR and Stc2 expression.
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Affiliation(s)
- Nikhil Y Patil
- Department of Pharmaceutical Sciences (N.Y.P., I.R., E.D., A.D.J.) and Harold Hamm Diabetes Center (A.M., J.E.F., A.D.J.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Iulia Rus
- Department of Pharmaceutical Sciences (N.Y.P., I.R., E.D., A.D.J.) and Harold Hamm Diabetes Center (A.M., J.E.F., A.D.J.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Emma Downing
- Department of Pharmaceutical Sciences (N.Y.P., I.R., E.D., A.D.J.) and Harold Hamm Diabetes Center (A.M., J.E.F., A.D.J.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Ashok Mandala
- Department of Pharmaceutical Sciences (N.Y.P., I.R., E.D., A.D.J.) and Harold Hamm Diabetes Center (A.M., J.E.F., A.D.J.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Jacob E Friedman
- Department of Pharmaceutical Sciences (N.Y.P., I.R., E.D., A.D.J.) and Harold Hamm Diabetes Center (A.M., J.E.F., A.D.J.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Aditya D Joshi
- Department of Pharmaceutical Sciences (N.Y.P., I.R., E.D., A.D.J.) and Harold Hamm Diabetes Center (A.M., J.E.F., A.D.J.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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Park H, Jin UH, Martin G, Chapkin RS, Davidson LA, Lee K, Jayaraman A, Safe S. Structure-activity relationships among mono- and dihydroxy flavones as aryl hydrocarbon receptor (AhR) agonists or antagonists in CACO2 cells. Chem Biol Interact 2022; 365:110067. [PMID: 35917944 PMCID: PMC9667734 DOI: 10.1016/j.cbi.2022.110067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 12/30/2022]
Abstract
Unsubstituted flavone induced CYP1A1, CYP1B1 and UGT1A1 gene expression in Caco2 cells and was characterized as an aryl hydrocarbon receptor (AhR) agonist. The structure-activity relationships among 15 mono- and dihydroxyflavones showed that addition of one or two hydroxyl groups resulted in active (e.g.: 5- and 6- mono- and 5,6-dihydroxyflavones) and inactive (e.g.: 7-mono, 7,4' and 6,4'-dihydroxyflavones) AhR ligands. Ligand docking studies of flavone, mono- and dihydroxyflavones to the human AhR resulted in similar docking scores that varied from -3.48 to -4.58 kcal/mol and these values did not distinguish between AhR-active and AhR-inactive mono- and dihydroxyflavones. The AhR-inactive flavones were subsequently investigated as AhR antagonists by determining their activities as inhibitors of TCDD-induced expression of CYP1A1, CYP1AA2 and UGT 1A1 gene expression in Caco2 cells. Initial studies with 7,4'-dihydroxyflavone showed that this compound was an AhR antagonist in Caco2 cells and resembled the activity of the classical AhR antagonist CH223191. With few exceptions most of the remaining AhR-inactive compounds in terms of inducing AhR responsive genes were also AhR antagonists. Thus, based on modeling studies, mono- and dihydroxyflavones bind with similar affinities to the AhR and exhibit AhR agonist or antagonist activities, however, the structural requirements (substitution patterns) for predicting these opposing activities were not apparent and could only be determined using bioassays.
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Affiliation(s)
- Hyejin Park
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843
| | - Un-Ho Jin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843
| | - Gregory Martin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX, USA, 77843
| | - Laurie A Davidson
- Department of Nutrition, Texas A&M University, College Station, TX, USA, 77843
| | - Kyongbum Lee
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, USA, 02155
| | - Arul Jayaraman
- Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, USA, 77843
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843.
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Coe KJ, Feinstein M, Higgins JW, Leung P, Scott BP, Skaptason J, Tam Y, Volak LP, Kinong J, Bittner A, McAllister H, Lim NM, Hack M, Koudriakova T. Characterization of JNJ-2482272 [4-(4-Methyl-2-(4-(Trifluoromethyl)Phenyl)Thiazole-5-yl) Pyrimidine-2-Amine] As a Strong Aryl Hydrocarbon Receptor Activator in Rat and Human. Drug Metab Dispos 2022; 50:1064-1076. [PMID: 35680134 DOI: 10.1124/dmd.121.000825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 05/18/2022] [Indexed: 11/22/2022] Open
Abstract
[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure after single administration (Cmax of 7.1 μM), JNJ-2482272 had plasma concentrations beneath the lower limit of quantification (3 ng/ml) after 6 consecutive days of dosing. To determine if JNJ-2482272 is an autoinducer in rats, plated rat hepatocytes were treated with JNJ-2482272 for 2 days. The major hydroxylated metabolites of JNJ-2482272 were isolated and characterized by mass spectrometry and NMR analyses. Compared with the vehicle-treated cells, a concentration-dependent increase was observed in the formation of phase I- and II-mediated metabolites coinciding with greater expression of cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) in rat hepatocytes. CYP1A1, CYP1A2, CYP1B1, and UGT1A6 transcripts were predominantly induced, suggesting that JNJ-2482272 is an activator of the aryl hydrocarbon receptor (AhR). In a human AhR reporter assay, JNJ-2482272 demonstrated potent AhR activation with an EC50 value of 0.768 nM, a potency more comparable to the strong AhR activator and toxin 2,3,7,8-tetrachloro-dibenzodioxin than to weaker AhR activators 3-methylcholanthrene, β-naphthoflavone, and omeprazole. In plated human hepatocytes, JNJ-2482272 induced CYP1A1 gene expression with an EC50 of 20.4 nM and increased CYP1A activity >50-fold from basal levels. In human recombinant P450s, JNJ-2482272 was exclusively metabolized by the CYP1 family of enzymes and most rapidly by CYP1A1. The summation of these in vitro findings bridges the in vivo conclusion that JNJ-2482272 is a strong autoinducer in rats and potentially in humans through potent AhR activation. SIGNIFICANCE STATEMENT: Drugs that induce their own metabolism (autoinducers) can lack sustained exposures for pharmacology and safety assessment hindering their development. JNJ-2482272 is demonstrated herein as a strong aryl hydrocarbon receptor (AhR) activator and CYP1A autoinducer, explaining its near complete loss of exposure after repeat administration in rat, which is likely translatable to human (if progressed further) considering its nanomolar potency comparable to "classical" AhR ligands like 2,3,7,8-tetrachloro-dibenzo-dioxin despite bearing a "nonclassical" drug structure.
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Affiliation(s)
- Kevin J Coe
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Mark Feinstein
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - J William Higgins
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Perry Leung
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Brian P Scott
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Judy Skaptason
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Yuen Tam
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Laurie P Volak
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Jennifer Kinong
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Anton Bittner
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Heather McAllister
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Nathan M Lim
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Michael Hack
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
| | - Tatiana Koudriakova
- Janssen Research & Development, L.L.C., San Diego, California (K.J.C., M.F., P.L., B.P.S., L.P.V., H.M., N.M.L., M.H., T.K.); Janssen Research & Development, L.L.C., San Francisco, California (Y.T.), Neurocrine Biosciences, Inc, San Diego, California (J.S.); Pfizer, San Diego, California (J.K.); Turnstone Biologics, La Jolla, California (A.B.); and Trestle Biotherapeutics, San Diego, California (J.W.H.)
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Madison CA, Kuempel J, Albrecht GL, Hillbrick L, Jayaraman A, Safe S, Chapkin RS, Eitan S. 3,3'-Diindolylmethane and 1,4-dihydroxy-2-naphthoic acid prevent chronic mild stress induced depressive-like behaviors in female mice. J Affect Disord 2022; 309:201-210. [PMID: 35461819 PMCID: PMC9153281 DOI: 10.1016/j.jad.2022.04.106] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 01/06/2022] [Accepted: 04/14/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Current pharmaceutical treatments for depression are sometimes ineffective and may have unwanted side effects that interfere with patient compliance. This study examined the potential antidepressant-like effects of dietary- and microbial-derived aryl hydrocarbon receptor (AhR) ligands, 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA). METHODS Female C57BL/6 mice were subjected to unpredictable chronic mild stress (UCMS) or were unstressed. For three weeks prior to UCMS mice were fed daily with vehicle or 20 mg/kg DIM, 1,4-DHNA or AhR-inactive isomer 3,7-DHNA; another group was subjected to two weeks UCMS before ligand administration began. Mice were examined for anhedonia-like behavior as measured by the sucrose preference test. Additionally, anxiety levels of the mice were examined before UCMS and ligand administration began and at the end in the open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests. At the end of the experiment they were also examined in the Morris water maze (MWM) task. RESULTS Both DIM and 1,4-DHNA, but not 3,7-DHNA, successfully prevented and reversed UCMS-induced anhedonia-like behavior. Furthermore, both DIM and DHNA had little to no effect on anxiety levels and did not induce spatial learning deficits. LIMITATIONS Additional studies are required to determine to what degree the antidepressant-like effects of DIM and 1,4-DHNA can be attributed to their activities as AhR ligands. CONCLUSIONS Our findings indicate that dietary and microbial-derived AhR ligands may have clinical applications as potential antidepressants. Future studies are necessary to elucidate the role of AhR in depression-like states and the underlying mechanisms of action.
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Affiliation(s)
- Caitlin A Madison
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Jacob Kuempel
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Georgia Lee Albrecht
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Lauren Hillbrick
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Shoshana Eitan
- Behavioral and Cellular Neuroscience, Department of Psychological and Brain Sciences, Texas A&M University, College Station, 4235 TAMU, TX 77843, USA.
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Groestlinger J, Spindler V, Pahlke G, Rychlik M, Del Favero G, Marko D. Alternaria alternata Mycotoxins Activate the Aryl Hydrocarbon Receptor and Nrf2-ARE Pathway to Alter the Structure and Immune Response of Colon Epithelial Cells. Chem Res Toxicol 2022; 35:731-749. [PMID: 35405071 PMCID: PMC9115800 DOI: 10.1021/acs.chemrestox.1c00364] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
After ingestion of food commodities, the gastrointestinal tract (GIT) poses the first barrier against xenobiotics and pathogens. Therefore, it is regularly confronted with external stressors potentially affecting the inflammatory response and the epithelial barrier. Alternaria mycotoxins such as alternariol (AOH) and altertoxin II (ATX-II) are frequently occurring food and feed contaminants that are described for their immunomodulatory capacities. Hence, this study aimed at exploring the effect of AOH and ATX-II as single compounds or binary mixtures on the immune response and epithelial homeostasis in noncancerous colon epithelial cells HCEC-1CT. Both toxins suppressed mRNA levels of proinflammatory mediators interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), and secretion of IL-8, as well as mRNA levels of the matrix metallopeptidase 2 (MMP-2). Binary combinations of AOH and ATX-II reduced the response of the single toxins. Additionally, AOH and ATX-II modified immunolocalization of transmembrane proteins such as integrin β1, zona occludens 1 (ZO-1), claudin 4 (Cldn 4), and occludin (Ocln), which support colonic tissue homeostasis and intestinal barrier function. Moreover, the cellular distribution of ZO-1 was affected by ATX-II. Mechanistically, these effects could be traced back to the involvement of several transcription factors. AOH activated the nuclear translocation of the aryl hydrocarbon receptor (AhR) and the nuclear factor erythroid 2-related factor 2 (Nrf2), governing cell metabolic competence and structural integrity. This was accompanied by altered distribution of the NF-κB p65 protein, an important regulator of inflammatory response. ATX-II also induced AhR and Nrf2 translocation, albeit failing to substantiate the effect of AOH on the colonic epithelium. Hence, both toxins coherently repress the intestinal immune response on the cytokine transcriptional and protein levels. Furthermore, both mycotoxins affected the colonic epithelial integrity by altering the cell architecture.
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Affiliation(s)
- Julia Groestlinger
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria
| | - Veronika Spindler
- Chair of Food Analytical Chemistry, Technical University of Munich, Maximus-von-Imhof-Forum 2, 85354 Freising, Germany
| | - Gudrun Pahlke
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria
| | - Michael Rychlik
- Chair of Food Analytical Chemistry, Technical University of Munich, Maximus-von-Imhof-Forum 2, 85354 Freising, Germany
| | - Giorgia Del Favero
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria.,Core Facility Multimodal Imaging, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria
| | - Doris Marko
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria
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El-Dairi R, Rysä J, Storvik M, Pasanen M, Huuskonen P. Aflatoxin B1 targeted gene expression profiles in human placental primary trophoblast cells. Curr Res Toxicol 2022; 3:100082. [PMID: 35814288 PMCID: PMC9263407 DOI: 10.1016/j.crtox.2022.100082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 11/25/2022] Open
Abstract
Gene expression profiles were studied in human primary trophoblast cells. 170 genes were significantly dysregulated in aflatoxin B1-exposed trophoblasts. AhR-mediated estrogen receptor signalling was dysregulated in response to AFB1. Transcripts involved in endocrine signalling and energy homeostasis were disrupted. Cellular growth and development, cell cycle and DNA repair processes were affected. Aflatoxin B1 (AFB1) is a mycotoxin produced by Aspergillus flavus and A. parasiticus. A high exposure (40 nM and 1 µM AFB1 for 72 h) was used to study mechanistic effects of AFB1 on gene expression patterns in human primary trophoblast cells, isolated from full term placentae after delivery. Gene expression profiling was conducted, and Ingenuity pathway analysis (IPA) software was used to identify AFB1-regulated gene networks and regulatory pathways. In response to 40 nM AFB1, only 7 genes were differentially expressed whereas 1 µM AFB1 significantly dysregulated 170 genes (124 down- and 46 upregulated, ±1.5-fold, p < 0.05) in AFB1-exposed trophoblasts when compared to controls. The top downregulated genes were involved in endocrine signalling and biosynthesis of hormones, and lipid and carbohydrate metabolism. The top upregulated genes were involved in protein synthesis and regulation of cell cycle. The main canonical pathways identified by IPA were associated with endocrine signalling including growth hormone signalling, and corticotropin releasing hormone signalling. Furthermore, genes involved in aryl hydrocarbon receptor (AhR)-mediated estrogen receptor signalling were dysregulated in response to AFB1. Our findings indicate that a high concentration 72 h AFB1 exposure caused relatively moderate number of changes on transcript level to human placental primary trophoblast cells. However, these preliminary results need to be confirmed with human-relevant concentrations of AFB1.
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Vazquez-Rivera E, Rojas B, Parrott JC, Shen AL, Xing Y, Carney PR, Bradfield CA. The aryl hydrocarbon receptor as a model PAS sensor. Toxicol Rep 2021; 9:1-11. [PMID: 34950569 PMCID: PMC8671103 DOI: 10.1016/j.toxrep.2021.11.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 11/19/2021] [Accepted: 11/24/2021] [Indexed: 01/02/2023] Open
Abstract
Proteins containing PER-ARNT-SIM (PAS) domains are commonly associated with environmental adaptation in a variety of organisms. The PAS domain is found in proteins throughout Archaea, Bacteria, and Eukarya and often binds small-molecules, supports protein-protein interactions, and transduces input signals to mediate an adaptive physiological response. Signaling events mediated by PAS sensors can occur through induced phosphorelays or genomic events that are often dependent upon PAS domain interactions. In this perspective, we briefly discuss the diversity of PAS domain containing proteins, with particular emphasis on the prototype member, the aryl hydrocarbon receptor (AHR). This ligand-activated transcription factor acts as a sensor of the chemical environment in humans and many chordates. We conclude with the idea that since mammalian PAS proteins often act through PAS-PAS dimers, undocumented interactions of this type may link biological processes that we currently think of as independent. To support this idea, we present a framework to guide future experiments aimed at fully elucidating the spectrum of PAS-PAS interactions with an eye towards understanding how they might influence environmental sensing in human and wildlife populations.
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Affiliation(s)
- Emmanuel Vazquez-Rivera
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Brenda Rojas
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Jessica C. Parrott
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Anna L. Shen
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Yongna Xing
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Patrick R. Carney
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Christopher A. Bradfield
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
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36
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Toxic Effects of Indoxyl Sulfate on Osteoclastogenesis and Osteoblastogenesis. Int J Mol Sci 2021; 22:ijms222011265. [PMID: 34681927 PMCID: PMC8538618 DOI: 10.3390/ijms222011265] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/17/2021] [Accepted: 10/18/2021] [Indexed: 02/07/2023] Open
Abstract
Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.
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Mertowska P, Mertowski S, Wojnicka J, Korona-Głowniak I, Grywalska E, Błażewicz A, Załuska W. A Link between Chronic Kidney Disease and Gut Microbiota in Immunological and Nutritional Aspects. Nutrients 2021; 13:3637. [PMID: 34684638 PMCID: PMC8540836 DOI: 10.3390/nu13103637] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is generally progressive and irreversible, structural or functional renal impairment for 3 or more months affecting multiple metabolic pathways. Recently, the composition, dynamics, and stability of a patient's microbiota has been noted to play a significant role during disease onset or progression. Increasing urea concentration during CKD can lead to an acceleration of the process of kidney injury leading to alterations in the intestinal microbiota that can increase the production of gut-derived toxins and alter the intestinal epithelial barrier. A detailed analysis of the relationship between the role of intestinal microbiota and the development of inflammation within the symbiotic and dysbiotic intestinal microbiota showed significant changes in kidney dysfunction. Several recent studies have determined that dietary factors can significantly influence the activation of immune cells and their mediators. Moreover, dietary changes can profoundly affect the balance of gut microbiota. The aim of this review is to present the importance and factors influencing the differentiation of the human microbiota in the progression of kidney diseases, such as CKD, IgA nephropathy, idiopatic nephropathy, and diabetic kidney disease, with particular emphasis on the role of the immune system. Moreover, the effects of nutrients, bioactive compounds on the immune system in development of chronic kidney disease were reviewed.
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Affiliation(s)
- Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Julia Wojnicka
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (J.W.); (A.B.)
| | - Izabela Korona-Głowniak
- Department of Pharmaceutical Microbiology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Anna Błażewicz
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (J.W.); (A.B.)
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, 8 Jaczewskiego Street, 20-954 Lublin, Poland;
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Han H, Safe S, Jayaraman A, Chapkin RS. Diet-Host-Microbiota Interactions Shape Aryl Hydrocarbon Receptor Ligand Production to Modulate Intestinal Homeostasis. Annu Rev Nutr 2021; 41:455-478. [PMID: 34633858 PMCID: PMC8667662 DOI: 10.1146/annurev-nutr-043020-090050] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds structurally diverse ligands and senses cues from environmental toxicants and physiologically relevant dietary/microbiota-derived ligands. The AhR is an ancient conserved protein and is widely expressed across different tissues in vertebrates and invertebrates. AhR signaling mediates a wide range of cellular functions in a ligand-, cell type-, species-, and context-specific manner. Dysregulation of AhR signaling is linked to many developmental defects and chronic diseases. In this review, we discuss the emerging role of AhR signaling in mediating bidirectional host-microbiome interactions. We also consider evidence showing the potential for the dietary/microbial enhancement ofhealth-promoting AhR ligands to improve clinical pathway management in the context of inflammatory bowel diseases and colon tumorigenesis.
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Affiliation(s)
- Huajun Han
- Program in Integrative Nutrition and Complex Diseases and Department of Nutrition, Texas A&M University, College Station, Texas 77843, USA;
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
| | - Stephen Safe
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, USA
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843, USA
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases and Department of Nutrition, Texas A&M University, College Station, Texas 77843, USA;
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
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Lim TX, Ahamed M, Reutens DC. The aryl hydrocarbon receptor: A diagnostic and therapeutic target in glioma. Drug Discov Today 2021; 27:422-435. [PMID: 34624509 DOI: 10.1016/j.drudis.2021.09.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 07/29/2021] [Accepted: 09/29/2021] [Indexed: 12/19/2022]
Abstract
Glioblastoma multiforme (GBM) is a deadly disease; 5-year survival rates have shown little improvement over the past 30 years. In vivo positron emission tomography (PET) imaging is an important method of identifying potential diagnostic and therapeutic molecular targets non-invasively. The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates multiple genes involved in immune response modulation and tumorigenesis. The AhR is an attractive potential drug target and studies have shown that its activation by small molecules can modulate innate and adaptive immunity beneficially and prevent AhR-mediated tumour promotion in several cancer types. In this review, we provide an overview of the role of the AhR in glioma tumorigenesis and highlight its potential as an emerging biomarker for glioma therapies targeting the tumour immune response and PET diagnostics.
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Affiliation(s)
- Ting Xiang Lim
- ARC Centre for Innovation in Biomedical Imaging Technology, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - Muneer Ahamed
- ARC Centre for Innovation in Biomedical Imaging Technology, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - David C Reutens
- ARC Centre for Innovation in Biomedical Imaging Technology, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.
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40
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Marszalek-Grabska M, Walczak K, Gawel K, Wicha-Komsta K, Wnorowska S, Wnorowski A, Turski WA. Kynurenine emerges from the shadows – Current knowledge on its fate and function. Pharmacol Ther 2021; 225:107845. [DOI: 10.1016/j.pharmthera.2021.107845] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022]
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41
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Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastroenterol Hepatol 2021; 18:559-570. [PMID: 33742166 PMCID: PMC7611426 DOI: 10.1038/s41575-021-00430-8] [Citation(s) in RCA: 211] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/09/2021] [Indexed: 02/01/2023]
Abstract
Mammalian aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that belongs to the basic helix-loop-helix (bHLH)-PAS family of transcription factors, which are evolutionarily conserved environmental sensors. In the absence of ligands, AHR resides in the cytoplasm in a complex with molecular chaperones such as HSP90, XAP2 and p23. Upon ligand binding, AHR translocates into the nuclear compartment, where it dimerizes with its partner protein, AHR nuclear translocator (ARNT), an obligatory partner for the DNA-binding and functional activity. Historically, AHR had mostly been considered as a key intermediary for the detrimental effects of environmental pollutants on the body. However, following the discovery of AHR-mediated functions in various immune cells, as well as the emergence of non-toxic 'natural' AHR ligands, this view slowly began to change, and the study of AHR-deficient mice revealed a plethora of important beneficial functions linked to AHR activation. This Review focuses on regulation of the AHR pathway and the barrier-protective roles AHR has in haematopoietic, as well as non-haematopoietic, cells within the intestinal microenvironment. It covers the nature of AHR ligands and feedback regulation of the AHR pathway, outlining the currently known physiological functions in immune, epithelial, endothelial and neuronal cells of the intestine.
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Affiliation(s)
| | | | - Emma Wincent
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
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Zablon HA, Ko CI, 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. [PMID: 34009372 PMCID: PMC8285021 DOI: 10.1093/toxsci/kfab050] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor well-known for its adaptive role as a sensor of environmental toxicants and mediator of the metabolic detoxification of xenobiotic ligands. In addition, a growing body of experimental data has provided indisputable evidence that the AHR regulates critical functions of cell physiology and embryonic development. Recent studies have shown that the naïve AHR-that is, unliganded to xenobiotics but activated endogenously-has a crucial role in maintenance of embryonic stem cell pluripotency, tissue repair, and regulation of cancer stem cell stemness. Depending on the cellular context, AHR silences the expression of pluripotency genes Oct4 and Nanog and potentiates differentiation, whereas curtailing cellular plasticity and stemness. In these processes, AHR-mediated contextual responses and outcomes are dictated by changes of interacting partners in signaling pathways, gene networks, and cell-type-specific genomic structures. In this review, we focus on AHR-mediated changes of genomic architecture as an emerging mechanism for the AHR to regulate gene expression at the transcriptional level. Collective evidence places this receptor as a physiological hub connecting multiple biological processes whose disruption impacts on embryonic development, tissue repair, and maintenance or loss of stemness.
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Affiliation(s)
| | | | - Alvaro Puga
- Department of Environmental and Public Health Sciences, Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
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43
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Wang A, Rojas O, Lee D, Gommerman JL. Regulation of neuroinflammation by B cells and plasma cells. Immunol Rev 2020; 299:45-60. [PMID: 33107072 DOI: 10.1111/imr.12929] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 09/07/2020] [Indexed: 02/06/2023]
Abstract
The remarkable success of anti-CD20 B cell depletion therapies in reducing the burden of multiple sclerosis (MS) disease has prompted significant interest in how B cells contribute to neuroinflammation. Most focus has been on identifying pathogenic CD20+ B cells. However, an increasing number of studies have also identified regulatory functions of B lineage cells, particularly the production of IL-10, as being associated with disease remission in anti-CD20-treated MS patients. Moreover, IL-10-producing B cells have been linked to the attenuation of inflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. In addition to IL-10-producing B cells, antibody-producing plasma cells (PCs) have also been implicated in suppressing neuroinflammation. This review will examine regulatory roles for B cells and PCs in MS and EAE. In addition, we speculate on the involvement of regulatory PCs and the cytokine BAFF in the context of anti-CD20 treatment. Lastly, we explore how the microbiota could influence anti-inflammatory B cell behavior. A better understanding of the contributions of different B cell subsets to the regulation of neuroinflammation, and factors that impact the development, maintenance, and migration of such subsets, will be important for rationalizing next-generation B cell-directed therapies for the treatment of MS.
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Affiliation(s)
- Angela Wang
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Olga Rojas
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Dennis Lee
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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44
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Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis. Int J Mol Sci 2020; 21:ijms21196996. [PMID: 32977499 PMCID: PMC7583016 DOI: 10.3390/ijms21196996] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023] Open
Abstract
Hematopoiesis is a complex and intricate process that aims to replenish blood components in a constant fashion. It is orchestrated mostly by hematopoietic progenitor cells (hematopoietic stem cells (HSCs)) that are capable of self-renewal and differentiation. These cells can originate other cell subtypes that are responsible for maintaining vital functions, mediate innate and adaptive immune responses, provide tissues with oxygen, and control coagulation. Hematopoiesis in adults takes place in the bone marrow, which is endowed with an extensive vasculature conferring an intense flow of cells. A myriad of cell subtypes can be found in the bone marrow at different levels of activation, being also under constant action of an extensive amount of diverse chemical mediators and enzymatic systems. Bone marrow platelets, mature erythrocytes and leukocytes are delivered into the bloodstream readily available to meet body demands. Leukocytes circulate and reach different tissues, returning or not returning to the bloodstream. Senescent leukocytes, specially granulocytes, return to the bone marrow to be phagocytized by macrophages, restarting granulopoiesis. The constant high production and delivery of cells into the bloodstream, alongside the fact that blood cells can also circulate between tissues, makes the hematopoietic system a prime target for toxic agents to act upon, making the understanding of the bone marrow microenvironment vital for both toxicological sciences and risk assessment. Environmental and occupational pollutants, therapeutic molecules, drugs of abuse, and even nutritional status can directly affect progenitor cells at their differentiation and maturation stages, altering behavior and function of blood compounds and resulting in impaired immune responses, anemias, leukemias, and blood coagulation disturbances. This review aims to describe the most recently investigated molecular and cellular toxicity mechanisms of current major environmental pollutants on hematopoiesis in the bone marrow.
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Safe S, Jin UH, Park H, Chapkin RS, Jayaraman A. Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs). Int J Mol Sci 2020; 21:6654. [PMID: 32932962 PMCID: PMC7555580 DOI: 10.3390/ijms21186654] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/01/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (U.-h.J.); (H.P.)
| | - Un-ho Jin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (U.-h.J.); (H.P.)
| | - Hyejin Park
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (U.-h.J.); (H.P.)
| | - Robert S. Chapkin
- Departments of Nutrition and Food Science and Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA;
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA;
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Aryl Hydrocarbon Receptor Connects Inflammation to Breast Cancer. Int J Mol Sci 2020; 21:ijms21155264. [PMID: 32722276 PMCID: PMC7432832 DOI: 10.3390/ijms21155264] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/12/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023] Open
Abstract
Aryl hydrocarbon receptor (AhR), an evolutionary conserved transcription factor, is a pleiotropic signal transductor. Thanks to its promiscuous ligand binding domain, during the evolution of eukaryotic cells its developmental functions were integrated with biosensor functions. Its activation by a multitude of endogenous and exogenous molecules stimulates its participation in several pathways, some of which are linked to inflammation and breast cancer (BC). Over time, the study of this malignancy has led to the identification of several therapeutic targets in cancer cells. An intense area of study is dedicated to BC phenotypes lacking adequate targets. In this context, due to its high constitutive activation in BC, AhR is currently gaining more and more attention. In this review, I have considered its interactions with: 1. the immune system, whose dysregulation is a renowned cancer hallmark; 2. interleukin 6 (IL6) which is a pivotal inflammatory marker and is closely correlated to breast cancer risk; 3. NF-kB, another evolutionary conserved transcription factor, which plays a key role in immunoregulatory functions, inflammatory response and breast carcinogenesis; 4. kynurenine, a tryptophan-derived ligand that activates and bridges AhR to chronic inflammation and breast carcinogenesis. Overall, the data here presented form an interesting framework where AhR is an interesting connector between inflammation and BC.
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Alternaria alternata Toxins Synergistically Activate the Aryl Hydrocarbon Receptor Pathway In Vitro. Biomolecules 2020; 10:biom10071018. [PMID: 32659980 PMCID: PMC7407958 DOI: 10.3390/biom10071018] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 06/28/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
Alternaria molds simultaneously produce a large variety of mycotoxins, of which several were previously reported to induce enzymes of phase I metabolism through aryl hydrocarbon receptor activation. Thus, we investigated the potential of naturally occurring Alternaria toxin mixtures to induce Cytochrome P450 (CYP) 1A1/1A2/1B1 activity. Two variants of an extract from cultured Alternaria alternata, as well as the toxins alternariol (AOH), alternariol monomethyl ether (AME), altertoxin I (ATX-I), and altertoxin II (ATX-II), were tested singularly and in binary mixtures applying the 7-ethoxy-resorufin-O-deethylase (EROD) assay in MCF-7 breast cancer cells. Sub-cytotoxic concentrations of the two toxin mixtures, as well as ATX-I, ATX-II and AOH, exhibited dose-dependent enhancements of CYP 1 activity. ATX-I and ATX-II interacted synergistically in this respect, demonstrating the two perylene quinones as major contributors to the extract’s potential. Binary mixtures between AOH and the two altertoxins respectively exhibited concentration-dependent antagonistic as well as synergistic combinatory effects. Notably, AME showed no efficacy towards EROD enzyme activity or impact on other toxins’ efficacy. Hence, this study provides insights into synergistic and other combinatory effects of Alternaria toxins in natural co-occurrence scenarios in the context of AhR signalling pathway activation in breast cancer cells.
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48
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Safe S, Jayaraman A, Chapkin RS. Ah receptor ligands and their impacts on gut resilience: structure-activity effects. Crit Rev Toxicol 2020; 50:463-473. [PMID: 32597352 PMCID: PMC7773274 DOI: 10.1080/10408444.2020.1773759] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/19/2020] [Accepted: 05/21/2020] [Indexed: 02/08/2023]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and structurally related halogenated aromatics modulate gene expression and induce biochemical and toxic responses that are mediated by initial binding to the aryl hydrocarbon receptor (AhR). The AhR also binds structurally diverse compound including pharmaceuticals, endogenous biochemicals, health-promoting phytochemicals, and microbial metabolites. Many of these AhR ligands do not induce TCDD-like toxic responses and some AhR ligands such as microbial metabolites of tryptophan play a role in maintaining gut health and protecting against intestinal inflammation and cancer. Many AhR ligands exhibit tissue- and response-specific AhR agonist or antagonist activities, and act as selective AhR modulators (SAhRMs) and this SAhRM-like activity has also been observed in AhR-ligand-mediated effects in the intestine. This review summarizes studies showing that several AhR ligands including phytochemicals and TCDD protect against dextran sodium sulfate-induced intestinal inflammation. In contrast, AhR ligands such as oxazole compounds enhance intestinal inflammation suggesting that AhR-mediated gut health can be enhanced or decreased by selective AhR modulators and this needs to be considered in development of AhR ligands for therapeutic applications in treating intestinal inflammation.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX, USA
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA
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Falandysz J, Smith F, Fernandes AR. Polybrominated dibenzo-p-dioxins (PBDDs) and - dibenzofurans (PBDFs) in cod (Gadus morhua) liver-derived products from 1972 to 2017. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 722:137840. [PMID: 32349199 DOI: 10.1016/j.scitotenv.2020.137840] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/11/2020] [Accepted: 03/08/2020] [Indexed: 06/11/2023]
Abstract
Literature data on the occurrence and prevalence of polybrominated dibenzo-p-dioxins (PBDDs) and polybrominated dibenzofurans (PBDFs) in foods including seafood are scarce. In this study, a number of cod-derived products including medicinal grade cod liver oils sourced from Northern Atlantic waters (Iceland, Norway) and the Baltic Sea (Poland) during 1972-2001 and canned cod liver sourced from the Baltic Sea in 2017, showed detectable levels of PBDFs: such as 2,3,8-TrBDF at 0.57 to 5.249 pg g-1 fat and 1,2,3,4,6,7,8-HpBDF at <0.018 to 0.302 pg g-1 fat. PBDDs were not detected in the cod liver oils. Canned cod liver products showed low levels of 2,3,7,8-TeBDD in the range <0.017 to 0.022 pg g-1 whole weight and 1,2,3,7,8-PeBDD at <0.03 to 0.039 pg g-1 whole weight. These concentrations were computed to yield upper bound toxic equivalences (TEQs) of 0.14 to 0.17 pg g-1 for the oils and 0.12 to 0.25 pg g-1 for the canned products (0.08 pg g-1 ww for both products). The resulting supplementary and dietary intakes are low (0.02 to 0.11 pg kg-1 bm day-1 for the oils and 0.07 to 0.17 pg kg-1 bm week-1 for the canned livers) in comparison to the recently expressed tolerable weekly intake of 2 pg kg-1 bm week-1. However, the intakes are underestimates, as due to a lack of analytical standards not all PBDD/F TEQ contributing congeners could be included. The PBDD/F TEQ contributes to the cumulative toxicity arising from other contaminants such as chlorinated dioxins and polychlorinated biphenyls.
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Affiliation(s)
- Jerzy Falandysz
- University of Gdańsk, Environmental Chemistry and Ecotoxicology, 80-308 Gdańsk, Poland; Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena, 130015 Cartagena, Colombia.
| | | | - Alwyn R Fernandes
- School of Environmental Sciences, University of East Anglia, Norwich NR4 7TJ, UK
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50
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Xi XX, Wang HL, Chen T, Dai JR, Hou SY, Chen YG. Prognostic value of preoperative serum bilirubin levels in ovarian cancer. Am J Transl Res 2020; 12:2267-2280. [PMID: 32509218 PMCID: PMC7269994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 04/30/2020] [Indexed: 06/11/2023]
Abstract
Bilirubin is a promising prognostic factor for non-liver disease-related deaths in various cancers. We investigated the association between preoperative serum bilirubin levels and oncological outcomes in patients with ovarian cancer. We retrospectively analyzed the clinical data of 282 patients with epithelial ovarian carcinoma (EOC), and grouped them according to optimal threshold values of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBL) measured by receiver operating characteristic curve analysis. Univariate and multivariate Cox proportional hazards regression analyses were used to evaluate various parameters that might affect overall survival (OS) and progression-free survival (PFS) in patients with EOC. The optimal cutoff values for TBIL, DBIL, and IBIL levels were 9.65 µmol/L, 2.95 µmol/L, and 6.75 µmol/L, respectively. Increased TBIL, DBIL, and IBIL levels correlated with the serum carbohydrate antigen (CA)-125 levels, International Federation of Gynecology and Obstetrics stage, and pathological differentiation (all P<0.05). Univariate analysis revealed longer OS and PFS in patients with high TBIL (≥9.65 µmol/L) and IBIL (≥6.75 µmol/L) levels (P<0.05). Multivariate analysis showed that patients with high IBIL levels (≥6.75 µmol/L) had significantly longer OS and PFS than those with low IBIL levels (<6.75 µmol/L) [hazard ratio (HR) = 0.333, 95% confidence interval (CI): 0.123~0.904, P<0.05; HR = 1.814, 95% CI: 1.169~2.816, P<0.05]. Therefore, IBIL is a potential independent prognostic factor for OS and PFS in patients with EOC. The higher the IBL level, the better the prognosis of patients with EOC.
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Affiliation(s)
- Xiao-Xue Xi
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, China
- Department of Obstetrics and Gynaecology, Suzhou Hospital Affiliated to Nanjing Medical University (Suzhou Municipal Hospital)Suzhou 215002, China
| | - Hui-Lin Wang
- Department of Obstetrics and Gynaecology, Suzhou Hospital Affiliated to Nanjing Medical University (Suzhou Municipal Hospital)Suzhou 215002, China
| | - Ting Chen
- Department of Obstetrics and Gynaecology, Suzhou Hospital Affiliated to Nanjing Medical University (Suzhou Municipal Hospital)Suzhou 215002, China
| | - Jian-Rong Dai
- Department of Obstetrics and Gynaecology, Suzhou Hospital Affiliated to Nanjing Medical University (Suzhou Municipal Hospital)Suzhou 215002, China
| | - Shun-Yu Hou
- Department of Obstetrics and Gynaecology, Suzhou Hospital Affiliated to Nanjing Medical University (Suzhou Municipal Hospital)Suzhou 215002, China
| | - You-Guo Chen
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, China
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