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
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Fangjie Wang,Sheng-Li Niu,Wei Li,Hong-Yuan Liu,Xue Gong,Xiaoyuan Ma,Bo Zhao,Dongmei He,Jinyu Xia,Liang Gong,Yiqin Cui,Rui Gao,Huaping Liang,Jing Gu,Qin Ouyang
Bacterial sepsis remains a leading cause of death globally, exacerbated by the rise of multidrug resistance (MDR). Host-directed therapy (HDT) has emerged as a promising nonantibiotic approach to combat infections; thus, multiple HDT targets have been identified. However, the translation of HDT targets into therapeutic drugs, particularly small-molecule drugs, remains rare. Our study focuses on cytochrome P4501A1 (CYP1A1), a negative regulator of host antiinfection capabilities. Using deep learning, virtual screening, and biological evaluation, we identified novel small-molecule inhibitors of CYP1A1. After structural optimization, compounds 38 and 47 demonstrated exceptional activity, reducing bacterial loads of methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii by over 70% by enhancing macrophage phagocytosis. This work highlights CYP1A1 as a valuable HDT target and shows that inhibiting it with a single small-molecule compound can offer a potential solution to treat MDR bacterial-induced sepsis.
研究领域:
感染与免疫
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药物开发
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分子生物学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2017
·Vol. 14
·期 5
·4174-4180
·
IF 1.261
Chuan‑Feng Huang,Wei‑Na Wang,Cheng‑Cao Sun,Yu‑Qing Wang,Ling Li,Yin Li,De‑Jia Li
The present study investigated the role of echinocystic acid (EA) on the expression of nuclear factor (NF)‑κB and cytochrome P450 1A1 (CYP1A1), and aortic morphology, in a rat model of hyperhomocysteinemia (Hhcy). A total of 50 Sprague Dawley rats were randomly divided into five groups as follows: Normal control (NC), model control (MC), vitamin control (VC; folic acid 1 mg/kg + vitamin B2 2 mg/kg + vitamin B12 10u g/kg), EA1 (20 mg/kg EA) and EA2 (40 mg/kg EA). Plasma homocysteine (Hcy) levels were determined via high performance liquid chromatography, and the morphology of the aorta was investigated using hematoxylin and eosin staining. Furthermore, aortic mRNA and protein levels of NF‑κB and CYP1A1 were measured using reverse transcription‑quantitative polymerase chain reaction analysis and western blotting, respectively. Plasma Hcy levels, and aortic mRNA and protein levels of NF‑κB and CYP1A1, were significantly lower in the EA‑treated group compared with the MC group (all P<0.05). However, the aortic morphology remained normal, including the endothelial cells of the inner layer, and smooth muscle cells of the media layer and adventitia. In conclusion, the results of the present study indicate that EA has a protective role on vascular endothelial cells in Hhcy through decreasing plasma Hcy, and thus NF‑κB and CYP1A1 expression.
研究领域:
药理学
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分子生物学
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心血管疾病
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2024
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IF 2.8
Gong Enhui,Pan Jiongwei,Ye Zaiting,Cai Xiaoping,Zheng Hao,Yin Zhangyong,Jiang Yiwei,Wang Xin,Cao Zhuo
ObjectivesReportedly, ganoderic acid A (GA-A) increases the sensitivity of hepatocellular carcinoma cells to cisplatin (DDP) chemotherapy. Therefore, this study aims to fathom the influence of GA-A on lung cancer cells.MethodsAfter the construction of A549/DDP cells through exposure to DDP, the effects of GA-A on A549 and A549/DDP cells were revealed by cellular functional assays, western blot and quantitative reverse transcription PCR (qRT-PCR). The DDP-resistant lung cancer tumor was established in vivo, followed by further validation of the mechanism of GA-A.ResultsGA-A suppressed the viability, migration, and invasion while downregulating Beclin and autophagy marker LC3II/LC3I levels and upregulating P62 levels in A549 and A549/DDP cells. These effects were reversed by circFLNA overexpression. Also, GA-A reinforced the sensitivity of A549/DDP cells to DDP, elevated the apoptosis and regulated the circFLNA/miR-486-3p/cytochrome P450 family 1 subfamily A member 1 (CYP1A1)/X-ray repair cross-complementing 1 (XRCC1) axis. The reversal effects of circFLNA overexpression on GA-A-induced viability and apoptosis of A549/DDP cells could all be counteracted in the presence of 3MA. GA-A inhibited lung cancer tumor growth and blocked autophagy.ConclusionGA-A suppresses autophagy by regulating the circFLNA/miR-486-3p/CYP1A1/XRCC1 axis to strengthen the sensitivity of lung cancer cells to DDP.
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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产品关联
DOI
PubMed
高影响因子
CANCER GENE THERAPY
·
2021
·Vol. 29
·期 1
·101-121
·
IF 5.987
Pan Jiongwei,Huang Gang,Yin Zhangyong,Cai Xiaoping,Gong Enhui,Li Yuling,Xu Cunlai,Ye Zaiting,Cao Zhuo,Cheng Wei
Significantly high-expressed circFLNA has been found in various cancer cell lines, but not in lung cancer. Therefore, this study aimed to explore the role of circFLNA in the progression of lung cancer. The target gene of circFLNA was determined by bioinformatics and luciferase reporter assay. Viability, proliferation, migration, and invasion of the transfected cells were detected by CCK-8, colony formation, wound-healing, and transwell assays, respectively. A mouse subcutaneous xenotransplanted tumor model was established, and the expressions of circFLNA, miR-486-3p, XRCC1, CYP1A1, and related genes in the cancer cells and tissues were detected by RT-qPCR, Western blot, or immunohistochemistry. The current study found that miR-486-3p was low-expressed in lung cancer. MiR-486-3p, which has been found to target XRCC1 and CYP1A1, was regulated by circFLNA. CircFLNA was located in the cytoplasm and had a high expression in lung cancer cells. Cancer cell viability, proliferation, migration, and invasion were promoted by overexpressed circFLNA, XRCC1, and CYP1A1 but inhibited by miR-486-3p mimic and circFLNA knockdown. The weight of the xenotransplanted tumor was increased by circFLNA overexpression yet reduced by miR-486-3p mimic. Furthermore, miR-486-3p mimic reversed the effect of circFLNA overexpression on promoting lung cancer cells and tumors and regulating the expressions of miR-486-3p, XRCC1, CYP1A1, and metastasis/apoptosis/proliferation-related factors. However, overexpressed XRCC1 and CYP1A1 reversed the inhibitory effect of miR-486-3p mimic on cancer cells and tumors. In conclusion, circFLNA acted as a sponge of miR-486-3p to promote the proliferation, migration, and invasion of lung cancer cells in vitro and in vivo by regulating XRCC1 and CYP1A1.
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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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
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
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
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2023
·Vol. 75
·期 3
·407-414
·
IF 3.3
Yin Xiaoting,Ma Suzhen,Li Mengyuan,Lu Shuaifei,Zhang Changjing,Liu Hui,Li Caiyin,Su Pan,Bai Ming,Li Yucheng
ObjectivesGefitinib is mainly used for the treatment of non-small-cell lung cancer. Hepatotoxicity is one of the main side effects of gefitinib, and seriously affects the treatment process of the disease. However, the hepatotoxicity mechanism of gefitinib remains unclear.MethodsThe hepatotoxicity of different doses of gefitinib was investigated in mice and AML-12 cells, and the possible correlation of hepatotoxicity with CYP450 was analysed.Key findingsThe toxic effects of gefitinib were confirmed by the increased liver index, decreased body weight and survival rate, injured liver function and histopathology followed 16 days of oral administration. Gefitinib (400 mg/kg) upregulated the hepatic mRNA expression of CYP1A1 and downregulated the CYP2D9 and CYP2D10 in mice. Furthermore, we verified that gefitinib produced cytotoxicity on AML-12 cells in a dose and time-dependent manner, and confirmed that gefitinib (20 μM) induced cell apoptosis, upregulated mRNA expression of CYP1A1 and downregulated CYP2D9 and CYP2D10. Pearson correlation analysis also showed that the hepatotoxicity of gefitinib was positively correlated with CYP1A1 and negatively correlated with CYP2D9 and CYP2D10.ConclusionsOur results suggested that the hepatotoxicity gefitinib may be associated with CYP1A1, CYP2D9 and CYP2D10. These findings will contribute to a better understanding of the mechanism of gefitinib hepatotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Hongyu Zhang,Guoshun Lin,Yifei Wang,Aihui Zheng,Hanlin Luo,Zhang Cao,Guige Hou,Yun Hou
Background Bisphenol S (BPS) is widely used in consumer products and food packaging, but its safety and potential risks have garnered increasing attention. Hydroxytyrosol (HT), a natural polyphenolic compound with potent antioxidant and anti-inflammatory activities, is yet to be investigated for its potential to reverse BPS-induced effects and the underlying mechanistic pathways. Methods The toxicological potential of BPS was assessed using the computational platform ProTox 3.0. Molecular experiments were performed to elucidate the effects of BPS on the nervous system. Protein-protein interaction networks were constructed to predict the targets of BPS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to explore the potential mechanisms of action, followed by molecular docking studies. We examined the therapeutic efficacy of HT against BPS-induced nerve damage using molecular assays and in vivo murine models. The key target identified by molecular docking was validated using RT-qPCR. Results Significant neurotoxic effects of BPS were identified using platform-based predictive analysis. The experimental results demonstrated that exposure to BPS not only reduced the viability of BV2 and HMC3 microglial and elevated intracellular reactive oxygen species (ROS) levels, but also induced a phenotypic shift in microglia toward a pro-inflammatory state, thereby may underscore its neurotoxic effects. Based on the results of the network toxicology analysis, BPS is potentially capable of exacerbating nerve damage via its modulatory effects, such as its modulation of cytochrome P450 Family 1 Subfamily A (CYP1A), like-CYP1A1, CYP1A2, and cytochrome P450 Family 2 Subfamily B6 (CYP2B6), etc. Finally, subsequent confirmation using network pharmacology and molecular docking analysis revealed that HT is capable of counteracting BPS-induced effects, and that CYP1A1 is highly likely to be a pivotal target implicated in both BPS-mediated toxicity in microglia and the therapeutic mechanisms of HT. This was further verified using RT-qPCR. Conclusion CYP1A1 is a critical mediator of BPS-induced toxicity and a potential therapeutic target of HT. These findings highlight the potential of natural compounds to mitigate environmental toxicant-induced neurological damage.
研究领域:
毒理学
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神经药理学
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环境健康
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分子生物学
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药学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2019
·Vol. 47
·期 8
·919-927
·
IF 3.354
Xu Mao,Jian Wang,Qian Wang,Lan Yang,Yilin Li,Hao Lin,Ying Peng,Jiang Zheng
The cytochrome P450 (P450) 1 family is an important phase I enzyme involved in carcinogen activation. Nitidine chloride (NC) is a pharmacologically active alkaloid with polyaromatic hydrocarbon found in the roots of Zanthoxylum nitidum (Roxb.) DC, a traditional medicinal herb widely used in China. We examined the inhibitory effects of NC on CYP1A1, 1B1, and 1A2. NC significantly inhibited CYP1A1- and 1B1-catalyzed ethoxyresorufin O-deethylation activity (IC50 = 0.28 ± 0.06 and 0.32 ± 0.02 μM, respectively) in a concentration-dependent manner, but only showed slight inhibition of CYP1A2 activity (IC50 > 50 μM). Kinetic analysis revealed that NC competitively inhibited CYP1B1 with a Ki value of 0.47 ± 0.05 μM, whereas NC caused a mixed type of inhibition on CYP1A1 with Ki and KI values of 0.14 ± 0.04 and 0.19 ± 0.09 μM, respectively. The observed enzyme inhibition neither required NADPH nor revealed time dependency. Molecular docking manifested the generation of strong hydrogen-bonding interactions of Ser116 in CYP1A1 and Ser127 in CYP1B1 with methoxy moiety of NC. Additionally, NC-induced alteration of estradiol (E2) metabolism was also investigated in the present study. Hydroxyestradiols, including 2-hydroxyestradiol [(2-OHE2) nontoxic] and 4-hydroxyestradiol [(4-OHE2) genotoxic] generated in recombinant enzyme incubation systems and cultured MCF-7 cells were analyzed, and NC was found to preferentially inhibit the nontoxic 2-hydroxylation activity of E2 mediated by CYP1A1. In conclusion, NC was a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. The remarkable inhibition on E2 2-hydroxylation might increase the risk of 4-OHE2–induced genotoxicity.
研究领域:
药理学
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毒理学
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生物化学
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酶学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Mei Wang,Na Luo,Yanpeng Gao,Guiying Li,Taicheng An
Derivatives of polycyclic aromatic hydrocarbons (PAHs) pose significant threat to environment and human health due to their widespread and potential hazards. However, adverse effects and action mechanisms of PAH derivatives on human health have not been attempted yet. Herein, we chose pyrene and its derivatives (1-hydroxypyrene, 1-nitropyrene, and 1-methylpyrene) to investigate adverse effect mechanism to human lungs using in vitro and in vivo methods. Results showed that pyrene derivatives have higher lung health risks than original pyrene. They can activate AhR, subsequently affecting expression of downstream target genes CYP1A1 and CYP1B1. The binding energies of pyrene and its derivatives ranged from −16.07 to −27.25 kcal/mol by molecular dynamics simulations, implying that pyrene and its derivatives acted as agonists of AhR and increased adverse effects on lungs. Specifically, 1-nitropyrene exhibited stabler binding conformation and stronger AhR expression. In addition, sensitivity of pyrene and its derivatives to AhR activation was attributed to type and number of key amino acids in AhR, that is, pyrene (Leu293), 1-nitropyrene (Cys333, Met348, and Val381), 1-hydroxypyrene (Leu293 and Phe287), and 1-methylpyrene (Met348). In summary, we provide a universal approach for understanding action mechanisms of PAH derivatives on human health, and their adverse effects should be taken seriously.
研究领域:
环境健康
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毒理学
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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
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Sili Chen,Xiangyu Ding,Tao Zheng,Hao Deng,Qiaoyuan Yang
Benzo[ghi]perylene (BghiP), a prevalent high-molecular-weight (HMW) polycyclic aromatic hydrocarbon (PAH) with significant environmental exposure, poses potential health risks that remain inadequately characterized. This study investigated the respiratory toxicity of BghiP exposure and its underlying mechanisms in vitro (human bronchial epithelial cells BEAS-2B and 16HBE) and in vivo (mouse model). Chronic exposure to environmentally relevant concentrations of BghiP (500 ng/mL for 2 weeks in vitro ; 500 µg/m 3 for 4 weeks in vivo ) significantly reduced cell proliferation, induced apoptosis and cell cycle arrest, and caused DNA damage in BEAS-2B and 16HBE cells. In vivo, BghiP exposure increased lung coefficients, induced pathological alterations, and triggered pulmonary inflammation. Mechanistically, BghiP exposure upregulated the expression of cytochrome P450 (CYP1A1), which subsequently promoted the transcription of chimeric RNA RPL17-C18orf32. We identified that the CYP1A1/RPL17-C18orf32 axis plays a pivotal role in mediating BghiP's toxic effects. Knockdown of either CYP1A1 or RPL17-C18orf32 attenuated BghiP-induced cytotoxicity, DNA damage, and cellular dysfunction, while overexpression of RPL17-C18orf32 exacerbated these detrimental effects. Co-manipulation experiments further confirmed that CYP1A1 acts upstream to regulate RPL17-C18orf32 expression. This study is the first to provide evidence that the CYP1A1/RPL17-C18orf32 axis is a critical mediator of BghiP-induced respiratory toxicity and DNA damage. Our findings systematically elucidate the cytotoxic and genotoxic effects of BghiP, introducing the novel concept of chimeric RNA involvement in PAH toxicity mechanisms and offering a new perspective for understanding the health impacts of environmental pollutants.
研究领域:
毒理学
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环境健康
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分子生物学
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遗传毒性
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呼吸系统
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）