BIOMEDICINE & PHARMACOTHERAPY
·
2025
·
IF 7.5
Yunqiu Chen,Jiayun Ying,Zhiyao Li,Zhen Ning Tony He,Jiani Zhan,Heng Liang,Yuying Liu,Yijia Chen,Xuewen Li,Ting Zhu,Chunxiang Kuang,Guoping Lu,Qing Yang
Indoleamine-2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in tryptophan (Trp) catabolism along kynurenine (Kyn) pathway. Increased IDO1 activity has been noticed in patients with sepsis, while IDO1’s involvement in sepsis, especially in the initial cytokine storm phase is not yet completely understood. Using the GEO database and clinical samples of sepsis, current study revealed that IDO1-AHR-CYP1A1 axis was significantly upregulated and closely related to cytokine storm in septic patients. With cell models of cytokine storm, it was found that IDO1 promoted cytokine storm and the apoptosis of model cells via AHR-CYP1A1, and IDO1-AHR-CYP1A1 axis correlated classic cytokine storm signal pathway including STAT3, NF-κB/STAT1, JNK/p38. With mouse models of septic cytokine storm, it was shown that IDO1 inhibitors could block the upregulated IDO1-AHR-CYP1A1 axis, reduce the enhanced inflammatory cytokine levels, decrease the phosphorylation of classic cytokine storm signal pathway, rescue organ damage, and increase survival rate. It was also found that IDO1 activation occurred after the increase of inflammatory cytokine levels. Therefore, classic cytokine storm signal pathways, inflammatory cytokines and IDO1-AHR-CYP1A1 axis form a tripartite interaction loop to promote cytokine storm. IDO1 inhibitors were able to block this process.
研究领域:
免疫学
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医学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Jiani Zhan,Yijia Chen,Yuying Liu,Yunqiu Chen,Zhiyao Li,Xuewen Li,Zhenning He,Fangzhou Meng,Xiaoyang Qian,Lili Yang,Qing Yang
Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 7
·786
·
IF 6
Tiantian Liu,Bin Jiang,Baoqiang Fu,Changyi Shang,Haobin Feng,Tao Chen,Yan Jiang
Previous research has established a correlation between PM2.5 exposure and aging-related cardiovascular diseases, primarily in blood vessels. However, the impact of PM2.5 on cardiomyocyte aging remains unclear. In this study, we observed that extractable organic matter (EOM) from PM2.5 exposure led to cellular senescence in H9c2 cardiomyoblast cells, as characterized by an increase in the percentage of β-galactosidase-positive cells, elevated expression levels of p16 and p21, and enhanced H3K9me3 foci. EOM also induced cell cycle arrest at the G1/S stage, accompanied by downregulation of CDK4 and Cyclin D1. Furthermore, EOM exposure led to a significant elevation in intracellular reactive oxygen species (ROS), mitochondrial ROS, and DNA damage. Supplementation with the antioxidant NAC effectively attenuated EOM-induced cardiac senescence. Our findings also revealed that exposure to EOM activated the aryl hydrocarbon receptor (AhR) signaling pathway, as evidenced by AhR translocation to the nucleus and upregulation of Cyp1a1 and Cyp1b1. Importantly, the AhR antagonist CH223191 effectively mitigated EOM-induced oxidative stress and cellular senescence. In conclusion, our results indicate that PM2.5-induced AhR activation leads to oxidative stress, DNA damage, and cell cycle arrest, leading to cardiac senescence. Targeting the AhR/ROS axis might be a promising therapeutic strategy for combating PM2.5-induced cardiac aging.
研究领域:
心血管疾病
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毒理学
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细胞生物学
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环境健康
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DOI
PubMed
高影响因子
Science Advances
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2024
·Vol. 10
·期 40
·
IF 11.7
Naming Wu,Jun Li,Lu Li,Liu Yang,Liyun Dong,Chen Shen,Shanshan Sha,Yangxue Fu,Enzhu Dong,Fang Zheng,Zheng Tan,Juan Tao
Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK+ macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK+ macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK+ macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti–programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.
研究领域:
免疫学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
·
IF 12.2
Meng-Die Li,Li-Hong Chen,Hui-Xian Xiang,Ya-Lin Jiang,Bian-Bian Lv,De-Xiang Xu,Hui Zhao,Lin Fu
Benzo[a]pyrene (BaP) and its metabolic end product benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE), are known toxic environmental pollutants. This study aimed to analyze whether sub-chronic BPDE exposure initiated pulmonary fibrosis and the potential mechanisms. In this work, male C57BL6/J mice were exposed to BPDE by dynamic inhalation exposure for 8 weeks. Our results indicated that sub-chronic BPDE exposure evoked pulmonary fibrosis and epithelial-mesenchymal transition (EMT) in mice. Both in vivo and in vitro , BPDE exposure promoted nuclear translocation of Snail. Further experiments indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) and p62 were upregulated in BPDE-exposed alveolar epithelial cells. Moreover, Nrf2 siRNA transfection evidently attenuated BPDE-induced p62 upregulation. Besides, p62 shRNA inhibited BPDE-incurred Snail nuclear translocation and EMT. Mechanically, BPDE facilitated physical interaction between p62 and Snail in the nucleus, then repressed Snail protein degradation by p62-dependent autophagy-lysosome pathway, and finally upregulated transcriptional activity of Snail. Additionally, aryl hydrocarbon receptor (AhR) was activated in BPDE-treated alveolar epithelial cells. Dual-luciferase assay indicated activating AhR could bind to Nrf2 gene promoter. Moreover, pretreatment with CH223191 or α-naphthoflavone (α-NF), AhR antagonists, inhibited BPDE-activated Nrf2-p62 signaling, and alleviated BPDE-induced EMT and pulmonary fibrosis in mice. Taken together, AhR-mediated Nrf2-p62 signaling contributes to BaP-induced EMT and pulmonary fibrosis.
研究领域:
毒理学
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肺科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
·
2025
·
IF 4.3
Wanglong Zhang,Yanjiao Zong,Ruize Sun,Zhenhong Xue,Wenhui Wan,Anran Ren,Yongchao Ma,Wenjing Tian,Renjun Wang
The global water pollution now calls for precise risk assessment of chemicals, e.g., dioxins and the dioxin-like compounds (DLCs). The freshwater and marine medaka have been widely implemented in the toxicity testing, and perhaps give mechanistic information for comparative biology. The question that ‘will they report equal results due to their close phylogenetic relation’ has been raised, therefore, we explored their physiological and molecular responses to dioxin. As the mediator of the dioxin toxicity, the aryl hydrocarbon receptor (AHR) of marine medaka ( Oryzias melastigma ) has not been functionally characterized and might be species-specific. In terms of sensitivity to dioxin—2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), the EC 50 values of omeAHR1a (0.16±0.12 nM), omeAHR1b (2.96±2.96 nM), omeAHR2a (0.44±0.30 nM), and omeAHR2b (9.00±6.88 nM) exhibit marked variations. The omeAHR2a and omeAHR1a display heightened sensitivity compared to the freshwater Japanese medaka ( Oryzias latipes ) counterparts olaAHR2a and olaAHR1a, respectively. The results indicate the in vitro sensitivity of AHR among species can vary by one or two orders of magnitude. Further mechanistic investigations using additional ligands and computational modeling reveal that: 1) most of omeAHR2a, olaAHR2a, dreAHR2, and hsaAHR interact with ligands in the affinity order of TCDD > PCB126 > BNF > indole, mirroring their AHR transactivation potency, but the docking poses and dynamics can vary; 2) one AHR subform's high sensitivity to dioxin—TCDD may extend to DLCs but not to other types of ligands. Beyond the in vitro study, the preliminary in vivo LC 50 data indicate that marine medaka (LC 50 : 1.64 ng/L (95% CI: 1.05-2.55 ng/L)) has similar sensitivity, and possibly slightly greater (not statistically determined yet), to TCDD in comparison with Japanese medaka (LC 50 : 3.42 ng/L (95% CI: 1.37-6.48 ng/L)).These insights underscore the difference of AHR biology among species even the close relative species, and point out the necessity for meticulous consideration when evaluating the toxicity of compounds and when extending predictive toxicity assessments to more species.
研究领域:
环境科学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Hongmei Zou,Mingxuan Zhang,Jin Chen,Stanley Aniagu,Yan Jiang,Tao Chen
Benzo[ a ]pyrene (BaP) is a representative polycyclic aromatic hydrocarbon widely present in the environment. We previously reported that the aryl hydrocarbon receptor (AHR) mediates BaP-induced apoptosis and cardiac malformations in zebrafish embryos, but the underlying molecular mechanisms were unclear. Since BaP is a mutagenetic compound, we hypothesize that BaP induces apoptosis and heart defects via AHR-mediated DNA damage. In this study, zebrafish embryos were exposed to BaP at a concentration of 0.1 μM from 2 to 72 h post fertilization, either with or without inhibitors/agonists. AHR activity and levels of reactive oxygen species (ROS) were examined under a fluorescence microscope. mRNA expression levels were quantified by qPCR. DNA damage and apoptosis were detected by immunofluorescence. Our findings revealed that BaP exposure significantly increased BPDE-DNA adducts, mitochondrial damage, apoptosis and heart defects in zebrafish embryos. These effects were counteracted by inhibiting AHR/cyp1a1 using pharmaceutical inhibitors or genetic knockdown. Furthermore, we observed that spironolactone, an antagonist of nucleotide excision repair (NER), significantly enhanced BaP-induced BPDE-DNA adducts, mitochondrial damage, apoptosis and heart malformation rates. Conversely, SRT1720, a SIRT1 agonist, reduced the adverse effects of BaP. Supplementation with spironolactone also enhanced γ-H2AX signals in the heart of zebrafish embryos exposed to BaP. Additional experiments demonstrated that BaP suppressed the expression of SIRT1. We further established that AHR, when activated by BaP, directly inhibited SIRT1 transcription, leading to downregulation of XPC and XPA, which are essential NER genes involved in the recognition and verification steps of the NER process. Taken together, our results indicate that AHR mediates BaP-induced DNA damage in the heart of zebrafish embryos by inducing BPDE-DNA adduct formation via the AHR/Cyp1a1 signalling pathway, as well as suppressing NER via AHR-mediated inhibition of SIRT1.
研究领域:
毒理学
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发育生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Shaoying Gong,Jiachen Zheng,Junjie Zhang,Jianchun Han
Benzo[ a ]pyrene (B[ a ]P), a kind of pollutant, can disrupt the gut microbiota, but its effects on the function of intestinal epithelial barrier (IEB) is still unclear. Arabinogalactan (AG), a natural polysaccharide, can protect intestinal tract. Thus, the purpose of this study was to evaluate the effect of B[ a ]P on IEB function and the mitigation effect of AG on the IEB dysfunction induced by B[ a ]P using a Caco-2 cell monolayer model. We found B[ a ]P could damage the IEB integrity by inducing cell cytotoxicity, increasing lactate dehydrogenase leakage, decreasing the transepithelial electrical resistance, and increasing fluorescein isothiocyanate-dextran flux. The mechanism of B[ a ]P-induced IEB damage may through induction of oxidative stress, including increasing reactive oxygen species levels, decreasing glutathione levels, reducing the activity of superoxide dismutase, and increasing malonaldehyde levels. Moreover, it can be due to increasing secretion of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α), down-regulated expression of tight junction (TJ) proteins (claudin-1, zonula occludens [ZO]-1, and occludin), and induced activation of aryl hydrocarbon receptor (AhR)/mitogen activated protein kinase (MAPK) signaling pathway. Remarkably, AG ameliorated B[ a ]P-induced IEB dysfunction through inhibited oxidative stress and pro-inflammatory factor secretion. Our study demonstrated B[ a ]P could damage the IEB and AG could alleviate this damage.
研究领域:
毒理学
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胃肠病学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
·
IF 6.1
Chao Hu,Yu-Xi Liu,Shi-Pang Zhang,Ya-Qi Wang,Ping Gao,Yu-Ting Li,Xue-Qing Yang
Aryl hydrocarbon receptor (AhR) enhances insect resistance to insecticides by regulating the detoxification network. Our previous studies have confirmed that overexpressions of cytochrome P450 monooxygenases (P450s) and glutathione S-transferases (GSTs) are involved in lambda-cyhalothrin resistance in Cydia pomonella. Here, we report that CpAhR regulates the expression of GST and P450 genes, thus conferring resistance. Expression patterns indicated that the expression of CpAhR was highly induced by lambda-cyhalothrin exposure and upregulated in a lambda-cyhalothrin-resistant population. RNA interference (RNAi) of CpAhR decreases the expression of key resistance-related genes (CpGSTe3, CpCYP9A121, and CpCYP9A122) and the activity of the GST enzyme, reducing the tolerance to lambda-cyhalothrin. Furthermore, β-naphthoflavone, a novel agonist of AhR, was first proven to be effective in increasing CpAhR expression and larval tolerance to lambda-cyhalothrin. These results demonstrate that CpAhR regulates the expression of key detoxifying genes and GST activity, resulting in the development of resistance to lambda-cyhalothrin in C. pomonella.
研究领域:
昆虫学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
BIOLOGY OF REPRODUCTION
·
2025
·
IF 3
Liao Shiying,Cheng Jinhua,Zhao Weimin,Dai Chaohui,Fu Yanfeng,Li Bixia,Deng Yanfei,Li Hui
Kynurenine (KYN) is a primary tryptophan derivative found in the human body and fermented foods. Previous studies have shown that KYN is an Aryl hydrocarbon receptor (AHR) agonist and is important in regulating various physiological activities, including female reproduction. Progesterone is a vital steroid hormone that facilitates embryo implantation and maintains pregnancy. However, whether KYN affects its biosynthesis remains unclear. To gain understanding, in vitro luteinized porcine granulosa luteal (pGL) cells were treated with KYN. The results showed that KYN disrupted progesterone biosynthesis by decreasing the expression of STAR and HSD3B in pGL cells. In addition, the expression of three transcription factors of STAR and HSD3B (GATA4, GATA6, and CEBPB) decreased after KYN treatment. Furthermore, the AHR blockade results showed comparable to those of KYN treatment, and subsequent knockdown experiments confirmed these results. These findings suggest that KYN inhibits progesterone biosynthesis in pGL cells by downregulating GATA4, GATA6, and CEBPB expression through AHR. Thus, our results showed for the first time, a previously unknown connection between KYN and progesterone biosynthesis.
研究领域:
生殖生物学
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内分泌学
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分子生物学
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DOI
PubMed
高影响因子
Food Frontiers
·
2024
·
IF 7.4
Hang Yu,Jingmin Fan,Rui Xue,Jiawei Guan,Fangyuan Tian,Yu Xu,Linyun He,Ji Liu,Zhenzhu Du,Daqun Chen,Wei Yu,Wen Chen,Bo Han
Alhagi honey (AH) is produced in arid and hot areas of Central Asia, and its polysaccharides (AP) are widely known for their activity in the treatment of intestinal diseases such as diarrhea. However, the therapeutic potential and mechanism of AP in ulcerative colitis (UC) remain unclear. Here, AH polysaccharide-2 (AP2), a polysaccharide with the highest content in AP, was isolated and evaluated for its effects on dextran sulfate sodium (DSS)-induced UC in mice. AP2 was found to alleviate UC symptoms and regulate gut microbiota dysbiosis by decreasing Helicobacter levels and increasing Lactobacillus levels. Analysis of PICRUSt2 predicted that AP2 may regulate carbohydrate and amino acid metabolism, and metabolomic analysis confirmed that AP2 promotes the metabolism of tryptophan to produce kynurenic acid (kyna). Moreover, kyna acted as an aryl hydrocarbon receptor (AhR) ligand, which activated AhR to increase the expression of the tight junction proteins claudin-1 and occludin. Interestingly, AP2 showed similar effects in protecting the intestinal barrier and alleviating colitis as the AhR agonist 6-formylindolo[3,2- b ]carbazole, and the AhR antagonist CH223191 partially blocked the therapeutic effect of AP2 in UC mice, indicating that the anti-UC effect of AP2 was AhR dependent. These findings demonstrate that AP2 alleviates UC by regulating the gut microbiota and promoting tryptophan metabolism to generate kyna-activated AhR. The insights gained from this study could help in the future development of AP2 as a drug candidate or functional food for the treatment of UC.
研究领域:
胃肠病学
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免疫学
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微生物学
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药理学
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产品关联
DOI
高影响因子
Arabian Journal of Chemistry
·
2023
·
IF 6
Peipei Zhou,Ying Kuang,Lihua Zuo,Shuhong Liang,Zhuolun Li,Lei Chen,Jingxue Li,Jun Zhang,Chenhan He,Xiaobao Wang,Yaojuan Chu,Jianying Pei,Zhi Sun,Shuzhang Du
Background Danshen Ligustrazine Injection (DSLI), composed of the extract of Salvia miltiorrhiza Bunge and Conioselinum anthriscoides 'Chuanxiong', is commonly used in the clinical treatment of ischemic stroke, which is the most common type of cerebrovascular disease, affected by multiple factors. The brain-gut axis is a new type of influencing factor for ischemic stroke, however, there is a lack of systematic research on the relationship between microbiota and host metabolic phenotype. This study aimed to investigate the host metabolic phenotype-microbiome interface in ischemic stroke and the immunomodulatory effects of DSLI. Methods In the study, liquid chromatography-mass spectrometry was used to primarily analyze the quality markers (Q-markers) and the polyphenols of DSLI. Based on 16S rRNA gene sequencing and metabolomics, the variations of microbial composition in different groups were characterized. In addition, a network diagram was constructed to reveal the interrelationship between DSLI-regulated gut microbiota changes and DSLI-regulated brain metabolites in MCAO/R rats. The expression of the aryl hydrocarbon receptor (AhR) in the colon and brain by immunofluorescence and suppressors of cytokine signaling 2 (SOCS2) by western blot were further detected. Results Diminished metabolic diversity and alterations in the tryptophan metabolism pathway were a feature of IS in the study. The results revealed that Clostri_UCG-014 was positively correlated with indoleacrylic acid, indole-3-methylacetate, and Ruminococcaceae was strongly related with L-tryptophan, 3-methylindole, and indole. The results of immunofluorescence showed that the expression of AhR in the colon and brain tissues of rats in the model group was greatly reduced compared with that in the sham-operated group, and was heavily activated with the treatment of DSLI. The levels of aryl hydrocarbon nuclear receptor ARNT2 and SOCS2 were down-regulated in the brains of Model rats, whereas increased by DSLI, further confirming that the brain-gut microbiota-Trp metabolism exists in the pathological changes of stroke and the intervention mechanism of DSLI. Conclusions The present study findings suggest Clostri_UCG-014, Ruminococcaceae, and Firmicute_RF39 play an important role in improving the regulation of immune function in stroke through tryptophan metabolites by acting on the AhR-SOCS2 axis.
研究领域:
药理学
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神经科学
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微生物学
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代谢组学
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免疫学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）