Antioxidants
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2024
·Vol. 13
·期 7
·827
·
IF 6
Baofu Xie,Yue Liu,Chunhong Chen,Tony Velkov,Shusheng Tang,Jianzhong Shen,Chongshan Dai
Colistin is commonly regarded as the “last-resort” antibiotic for combating life-threatening infections caused by multidrug-resistant (MDR) gram-negative bacteria. Neurotoxicity is a potential adverse event associated with colistin application in clinical settings, yet the exact molecular mechanisms remain unclear. This study examined the detrimental impact of colistin exposure on PC12 cells and the associated molecular mechanisms. Colistin treatment at concentrations of 0–400 μM decreased cell viability and induced apoptotic cell death in both time- and concentration-dependent manners. Exposure to colistin triggered the production of reactive oxygen species (ROS) and caused oxidative stress damage in PC12 cells. N-acetylcysteine (NAC) supplementation partially mitigated the cytotoxic and apoptotic outcomes of colistin. Evidence of mitochondrial dysfunction was observed through the dissipation of membrane potential. Additionally, colistin treatment upregulated the expression of AhR and CYP1A1 mRNAs in PC12 cells. Pharmacological inhibition of AhR (e.g., using α-naphthoflavone) or intervention with the CYP1A1 gene significantly decreased the production of ROS induced by colistin, subsequently lowering caspase activation and cell apoptosis. In conclusion, our findings demonstrate, for the first time, that the activation of the AhR/CYP1A1 pathway contributes partially to colistin-induced oxidative stress and apoptosis, offering insights into the cytotoxic effects of colistin.
研究领域:
药理学
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毒理学
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细胞生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
Discover Oncology
·
2025
·Vol. 16
·期 1
·1-18
·
IF 2.9
Guo Lin,Zhang Jia,Li Yuqiang,Gao Yuehong,Huang Jiali,Liu Mengru,Li Jing,Chai Wenshu,Li Yubin
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. In lung cancer, AHR activation stimulates cancer cell proliferation and promotes tissue invasion and metastasis, and targeting the AHR pathway is an effective way to prevent and treat lung cancer. In lung cancer, AHR binds to the NRF2 promoter region to promote carcinogenesis, but treatment research based on AHR/NRF2 pathway is insufficient. 3,3′-diindolylmethane (DIM), an active phytochemical derivative extracted from cruciferous vegetables, is a modulator of AHR. In this study, We investigated the medicinal value of DIM in NSCLC (non-small cell lung cancer) by in vivo and in vitro experiments and explored the underlying mechanisms. In vitro studies showed that DIM inhibited the viability of NSCLC and induced apoptosis and cycle arrest in cancer cells. DIM inhibited the migration and invasion of NSCLC cells by reversing the epithelial-mesenchymal transition. DIM induced ferroptosis in NSCLC cells; increased cellular Fe 2+ , ROS (reactive oxygen species), and MDA; decreased cellular GSH, AHR, NRF2, and GPX4; and disrupted the mitochondrial membrane potential. The effect of DIM-induced ferroptosis can be reversed by the AHR receptor antagonist CH-223191, ferroptosis inhibitor Fer-1, and ROS scavenger NAC. Overexpression of NRF2 reversed DIM-induced ferroptosis. Identical results were obtained in a nude mouse xenograft model. In summary, we have confirmed that DIM has significant potential in the treatment of non-small cell lung cancer. DIM induces cancer cell ferroptosis through the AHR/NRF2/GPX4 axis. These findings provide experimental basis for DIM treatment and future clinical research in non-small cell lung cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2021
·
IF 4.221
Yujie Huang,Jie Zhang,Yizhou Tao,Cheng Ji,Stanley Aniagu,Yan Jiang,Tao Chen
Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon, is widely present in the environment. BaP-induced heart defects have been frequently reported, but the underlying molecular mechanisms remain elusive. Here, we found that BaP increased heart malformations in zebrafish embryos in a concentration-dependent manner, which were attenuated by supplementation with either CH223191 (CH), an aryl hydrocarbon receptor (AHR) inhibitor, or N-acetyl- l -cysteine (NAC), a reactive oxygen species (ROS) scavenger. While CH and NAC both inhibited BaP-induced ROS generation, NAC had no effect on BaP-induced AHR activation. We further demonstrated that BaP increased mitochondrial ROS, decreased mitochondrial membrane potential, and caused endogenous apoptosis, with all these effects being counteracted by supplementation with either CH or NAC. Resveratrol (RSV), a natural AHR antagonist and ROS scavenger, also counteracted the heart malformations caused by BaP. Further experiments showed that RSV attenuated BaP-induced oxidative stress, mitochondrial damage and apoptosis, but had no significant effect on AHR activation. In conclusion, our findings show that BaP induces oxidative stress via AHR activation, which causes mitochondria-mediated intrinsic apoptosis, resulting in heart malformations in zebrafish embryos, and that RSV had a protective effect against BaP-induced heart defects mainly by inhibiting oxidative stress rather than through antagonism of AHR activity.
研究领域:
环境毒理学
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心血管发育
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Linlin Ding,Qingjie Li,Kaige Qi,Yonghui Chen,Na Hu,Sangyu Hu,Tianqi Fang,Shuang Guan,Jianfeng Wang,Jiazhang Qiu,Xuming Deng,Lei Xu
Background Salmonella pullorum ( S. pullorum ) is an enteric pathogen that impairs growth performance, leading to substantial economic losses. Evidence demonstrates that the natural flavonoid phloretin can modulate intestinal microbiota functionality, and which underpins its therapeutic efficacy in ameliorating gastrointestinal disorders. However, the protective effects of phloretin against S. pullorum infections and underlying mechanisms remain unelucidated. Purpose This study aimed to elucidate the protective effects and mechanisms of phloretin in improving defense against S. pullorum infection by modulating gut microbiota in chicks. Methods H&E staining, RT-qPCR and ELISA assays were used to assess the protective potentials of phloretin in S. pullorum -infected chicks. Then, 16S rRNA gene sequencing and untargeted metabolomics were employed to identify key microbiota and metabolites regulating the intestinal microenvironment. Moreover, fecal microbiota transplantation (FMT) and dietary metabolite supplementation were conducted to reshape the gut microbiota, elucidate the interaction between the microbiota and S. pullorum infection. Results Phloretin treatment alleviated intestinal injury and enhanced growth performance in S. pullorum -infected chicks via improved intestinal barrier integrity, suppression of inflammatory responses, and restructuring of gut microbial composition. Additionally, these beneficial effects were also observed following FMT from phloretin-treated donors. Subsequent microbial and untargeted metabolomic analysis revealed that phloretin significantly enriched abundance of the functional bacterium Faecalibacterium , and the microbiota-derived phenylalanine metabolites 3-phenylpropionic acid (3-PPA). Importantly, 3-PPA supplementation attenuates S. pullorum -induced intestinal barrier damaged and inflammation in chicks through modulation of the AhR/IL-22/STAT-3 signalling axis. Conclusion These findings provide new insights into the therapeutic potentials of phloretin for S. pullorum -infected chicks.
研究领域:
微生物学
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免疫学
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分子生物学
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兽医学
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代谢组学
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药理学
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DOI
PubMed
高影响因子
PEST MANAGEMENT SCIENCE
·
2019
·Vol. 75
·期 7
·2009-2019
·
IF 3.255
Bo Hu,He Huang,Qi Wei,Miaomiao Ren,David K Mburu,Xiangrui Tian,Jianya Su
BACKGROUND Glutathione S -transferases (GSTs) are a superfamily of multifunctional dimeric proteins existing in both prokaryotic and eukaryotic organisms. They are involved in the detoxification of both endogenous and exogenous electrophiles, including insecticides. However, the molecular mechanisms underlying the regulation of GST genes in insects are poorly understood. RESULTS We first identified at least three GST genes involved in resistance to the insecticides chlorpyrifos and cypermethrin. Analysis of upstream sequences revealed that three GSTs ( SeGSTo2 , SeGSTe6 and SeGSTd3 ) harbor the same cap ‘n’ collar C/muscle aponeurosis fibromatosis (CncC/Maf) binding site, and SeGSTo2 and SeGSTe6 contain the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AhR/ARNT) binding site. Luciferase reporter assay showed co-transfection of reporter plasmid containing the SeGSTe6 promoter with CncC and/or Maf expressing constructs significantly boosted transcription. Similarly, AhR and/or ARNT expressing constructs also significantly increased the promoter activities. The co-transfection of mutated reporter plasmid with CncC/Maf or AhR/ARNT did not increase transcription activity anymore. Constitutive over-expression of CncC, Maf and AhR was also found in the HZ16 strain, which might be the molecular mechanism for up-regulated expression of multiple detoxification genes conferring resistance to insecticides. CONCLUSION These results suggest that CncC/Maf and AhR/ARNT coordinately regulate the expression of multiple GST genes involved in insecticide resistance in Spodoptera exigua . © 2019 Society of Chemical Industry
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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基因组学
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2021
·
IF 4.374
Jinwen Yuan,Xiaoming Sun,Siyan Che,Li Zhang,Zheng Ruan,Xiaomin Li,Junhua Yang
Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants. They are constantly detected in terrestrial, ocean, and atmospheric systems, and it is of particular concern that these fat-soluble xenobiotics may have a negative impact on human health. This study aimed to evaluate the toxic effect and underlying mechanism of decabromodiphenyl ether (BDE-209) on human liver in a HepG2 cell model. The results showed that BDE-209 significantly induced HepG2 cells apoptosis, increased intracellular reactive oxygen species (ROS), disturbed [Ca 2+ ] homeostasis and mitochondrial membrane potential (MMP), and caused nuclear shrinkage and DNA double-strand breaks. BDE-209 also significantly decreased the activities of antioxidant parameters, superoxide dismutase (SOD), total antioxygenic capacity (T-AOC), glutathione (GSH), and total glutathione (T-GSH). The up-regulation of the Aryl hydrocarbon receptor (AhR)/cytochrome P4501A1 (CYP1A1) signaling pathway indicates that after long-term and high-dose exposure, BDE-209 may be a liver carcinogen. Interestingly, HepG2 cells attempt to metabolize BDE-209 through the Nrf2-mediated antioxidant pathway. These findings help elucidate the mechanisms of BDE-209-induced hepatotoxicity in humans.
研究领域:
毒理学
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环境科学
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PLoS Neglected Tropical Diseases
·
2024
·Vol. 18
·期 12
·e0012714
·
IF 3.4
Xuanyin Cui,Yi Cheng,Hongyan Wang,Xiaomao Li,Jinfu Li,Ke Zhang,Rong Mou
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with an unknown etiology and is difficult to treat. Studies have shown that some helminths and their associated products have therapeutic potential in controlling or preventing inflammatory diseases. This study is to investigate the mitigation effects of Hymenolepis nana antigens (HnAg) on the UC model. HnAg significantly improved the disease activity index, colon length, and colonic pathological damage in mice with dextran sulfate sodium (DSS)-induced colitis. HnAg intervention could protect the number of goblet cells and enhance the expression of tight junction proteins and mucins, thereby improving intestinal barrier integrity. HnAg attenuated small intestinal organoid damage and stimulated intestinal stem cells proliferation in a DSS-induced mouse organoid inflammation model. The protective mechanism of HnAg might be related to the activation of the aryl hydrocarbon receptor (AhR)/IL-22 signaling pathway, which regulates intestinal barrier function and promotes the proliferation and differentiation of intestinal stem cells. In conclusion, HnAg has a therapeutic effect on UC mice. Our study provides a new approach for alleviating UC by Hymenolepis nana and its associated products.
Ulcerative colitis (UC) is an immune-mediated chronic inflammatory disease. Currently, commonly used drugs such as aminosalicylates and glucocorticosteroids are difficult to treat and have many adverse effects. In recent years, there has been a growing interest in utilizing the immunomodulatory abilities of worms to develop new therapies for the treatment of inflammatory and allergic diseases. Hymenolepis nana is a zoonotic parasitic worm that parasitizes the small intestines of humans and rodents and generally does not cause serious pathologic damage to their hosts, making it a potential class of intestinal parasites in helminthic therapy. In this study, we investigated the mitigating effect of Hymenolepis nana antigens (HnAg) on UC in mice from the perspective of maintaining intestinal mucosal barrier integrity. The results showed that HnAg alleviated UC in mice by activating the aryl hydrocarbon receptor (AhR)/IL-22 signaling pathway, promoting the proliferation and differentiation of intestinal stem cells, and modulating the integrity of the intestinal mucosal barrier. Meanwhile, HnAg attenuated DSS-induced inflammatory damage in mouse small intestinal organoid tissues and promoted intestinal stem cells proliferation. Suggesting that Hymenolepis nana and its related products may become a new option for alleviating UC.
研究领域:
免疫学
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胃肠病学
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药理学
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炎症性肠病
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Arong Wang,Cheng Guan,Tieqi Wang,Guangqing Mu,Yanfeng Tuo
Our previous studies have shown that Lactiplantibacillus plantarum DPUL-S164-derived indole-3-lactic acid (ILA) ameliorates intestinal epithelial cell barrier injury by activating aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways and promoting tight junction protein expression. This study further explored the crucial substances of L. plantarum DPUL-S164 in alleviating intestinal barrier damage in mice through a dextran sodium sulfate-induced ulcerative colitis mouse model. Compared to dead L. plantarum DPUL-S164 (D-S164), live L. plantarum DPUL-S164 (S164) and its tryptophan metabolite, ILA, showed an effective ameliorating effect on the intestinal barrier injury of mice treated by antibiotic cocktail and sodium dextran sulfate, suggesting that the crucial substances of L. plantarum DPUL-S164 ameliorating intestinal barrier injury are its extracellular metabolites. Furthermore, S164 and its tryptophan metabolite, ILA, ameliorate intestinal barrier injury and suppress intestinal inflammation by activating the AhR–Nrf2 pathway and inhibiting the nuclear factor kappa-B (NF-κB) pathway. These results suggest that L. plantarum DPUL-S164 ameliorates intestinal epithelial barrier damage in mice, primarily by producing ILA as a ligand to activate the AhR pathway.
研究领域:
微生物学
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免疫学
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胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biochemistry and Cell Biology
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2024
·
IF 2.4
Xiang Chen,Yuan Yao,Guotong Gong,Tianji He,Chenjun Ma,Jingsong Yu
Prostate cancer (PCa) is a complex disease with diverse molecular alterations. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that exhibits pleiotropic roles in PCa, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR. While targeting ferroptosis is an innovative PCa therapeutic strategy, the impact of AhR on this process remains unclear. This study aimed to investigate the influence of AhR on lipid peroxidation and ferroptosis. Results showed that TCDD activated AhR, as evidenced by increased CYP1A1 expression, leading to reduced cell viability. TCDD caused mitochondria shrinkage, decreased the GSH/GSSG ratio, and elevated the MDA levels and lipid peroxidation. Interestingly, AhR knockdown reversed these effects, similar to the action of ferroptosis inhibitors. Mechanistically, TCDD suppressed nuclear receptor subfamily 4 group A member 1 (NR4A1) expression, in part due to AhR activation. This suppression subsequently led to a reduction in the expression of the NR4A1 downstream target stearoyl-CoA desaturase 1 (SCD1). NR4A1 overexpression counteracted the effects of TCDD. In vivo, TCDD activated AhR, downregulated NR4A1 and SCD1 expression, induced mitochondria shrinkage, and increased the MDA and 4-hydroxynonenal (4-HNE) levels. In summary, TCDD promotes ferroptosis in androgen-dependent PCa via inhibiting the NR4A1/SCD1 axis, in part dependent on AhR activation.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Mingxia Ma,Yanxin Wang,Siqing Fan,Yumeng Huang,Xiurong Su,Chenyang Lu
Urolithin A (UroA) is a microbial metabolite derived from ellagitannins and ellagic acid with good bioavailability. In this study, we explored the anticolitis activity of UroA and clarified the mechanism by 16S rDNA sequencing and metabonomics. UroA alleviated dextran sulfate sodium (DSS)-induced colitis in mice, characterized by a decreased disease activity index, increased colon length, and improved colonic histopathological lesions, along with inhibited phosphorylation of the mitogen-activated protein kinase signaling pathway. In addition, UroA improved gut microbiota dysbiosis and modulated the microbiota metabolome. Furthermore, targeted metabolomics focused on tryptophan catabolites showed that UroA significantly increased the production of indole-3-aldehyde (IAld) and subsequently led to increased colonic expression of aryl hydrocarbon receptor (AhR) and promoted the serum content of IL-22 in mice with colitis. Collectively, our data identified a novel anticolitis mechanism of UroA by improving gut microbiota dysbiosis, modulating microbial tryptophan metabolism, promoting IAld production, and triggering AhR/IL-22 axis activation. However, a limitation noted in this study is that these beneficial effects of UroA were found at 50 μM in vitro and 20 mg/kg in vivo, which were nonphysiological concentrations.
研究领域:
药理学
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免疫学
·
微生物学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2023
·
IF 6.1
Jiachen Zhuang,Qianqian Wang,Fei Shen,Jing Wang,Juan Du,Peng Yu,Fengqin Feng,Minjie Zhao
This study investigated the immunomodulatory effects of soft-shelled turtle (Pelodiscus sinensis) peptide (TP) and Chinese pond turtle (Chinemys reevesii) peptide (TMP) on the intestinal mucosal immune system (IMIS). The results demonstrated that TP and TMP improved holistic immunity by restoring the vital immune organ atrophy and proliferation capacity of spleen immune cells. Moreover, TP and TMP significantly increased the serum content of IgA and cytokines that are responsible for immune cell activation and antigen clearance. TP and TMP promoted intestinal B cell activation, class switching recombination, and antibody secreting processes in a T cell-independent manner to increase the SIgA content. Furthermore, TP and TMP enhanced the intestinal barrier by increasing the protein expression of tight junctions (TJs) and adhesion junctions (AJs) and ameliorating the intestinal morphology. Mechanistically, TP and TMP activated the AHR/IL-22/STAT3/IL-6 axis to enhance the IgA response and improve the intestinal barrier, indicating their potential in intestinal health modulation.
研究领域:
免疫学
·
胃肠病学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Lei Li,Guojun He,Mingyu Shi,Juehua Zhu,Yongqing Cheng,Yang Chen,Jin Chen,Qun Xue
Cerebral small vessel disease (CSVD) is one of the most important causes of stroke and vascular dementia , so exploring effective treatment modalities for CSVD is warranted. This study aimed to explore the anti-inflammatory effects of Edaravone dexborneol (C.EDA) in a CSVD model. Mice with CSVD showed distinct cognitive decline, as assessed by the Morris water maze (MWM). Pathological staining verified leakage across the blood‒brain barrier (BBB), microglial proliferation, neuronal loss and demyelination . Western blot analysis demonstrated that M1 microglia dominated prophase and released proinflammatory molecules; the aryl hydrocarbon receptor (AHR) was found to participate in modulating nuclear factor-kappa B (NF-κB) signalling activation through tumour necrosis factor receptor-associated factor-6 (TRAF6). C.EDA treatment resulted in the polarization of microglia from the M1 to the M2 phenotype. Mice sequentially treated with C.EDA exhibited a significant improvement in cognitive function; expression of the anti-inflammatory cytokines and modulatory proteins AHR and TRAF6 was upregulated, while the levels of pNF-κBp65 and pIΚBα were downregulated. C.EDA promoted microglial activation towards the M2 phenotype by upregulating AHR expression, which prevented TRAF6 ubiquitination , promoted NF-κB RelA/p65 protein degradation and inhibited subsequent NF-κB phosphorylation. Mechanistically, the anti-inflammatory effect of C.EDA alleviated neuronal loss and myelin damage, while at the functional level, C.EDA improved cognitive function and thus showed good application prospects.
研究领域:
神经科学
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药理学
·
神经退行性疾病
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炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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