ENVIRONMENTAL TOXICOLOGY
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2023
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IF 4.5
Yuhong Kou,Yongping Chen,Tongtong Feng,Luomeng Chen,Hui Wang,Ning Sun,Shuping Zhao,Tianyuan Yang,Wenjing Jiao,Guofeng Feng,Honggang Fan,Yuan Zhao
Glufosinate-ammonium (GLA) is a widely used herbicide, but less research has been done on its harmful effects on non-target organisms, especially aquatic organisms. In this study, 600 adult zebrafish were exposed to different concentration of GLA (0, 1.25, 2.5, 5, 10, and 20 mg/L) for 7 days, and the livers were dissected on the eighth day to examine the changes in liver structure, function, oxidative stress, inflammation, apoptosis, and Nrf2 pathway, and finally to clarify the mechanism of GLA induced liver injury in zebrafish. The levels of alanine aminotransferase, aspartate aminotransferase, reactive oxygen species, malondialdehyde, inflammatory factors (IL-6 and TNF-α), and caspase-3 gradually increased, while the levels of superoxide dismutase, catalase, glutathione, and glutathione peroxidase gradually decreased with the increase of GLA concentration. The Nrf2 pathway was activated at low concentrations (1.25–5 mg/L) and significantly inhibited at high concentrations (10 and 20 mg/L). These results suggested that GLA could cause oxidative stress, inflammation, and apoptosis in zebrafish liver. Therefore, GLA can cause liver injury in zebrafish, and at high concentrations, the inhibition of Nrf2 pathway is one of the important causes of liver injury.
研究领域:
水生毒理学
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环境科学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Environmental Research and Public Health
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2019
·Vol. 17
·期 1
·138
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IF 2.468
Chang Liu,Yaohui Zhu,Zhenxiang Lu,Weina Guo,Bayaer Tumen,Yalan He,Chao Chen,Shanshan Hu,Kangzhi Xu,Yan Wang,Lei Li,Shenghe Li
Acute Cadmium (Cd) exposure usually induces hepatotoxicity. It is well known that oxidative stress and inflammation causes Cd-induced liver injury. However, the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) in Cd-induced liver injury is not completely understood. In this study, we observed Cd-induced liver damage and the potential contribution of Nrf2, nuclear factor-κB (NF-κB), Nod-like receptor 3 (NLRP3), and mitogen-activated protein kinases (MAPKs) signaling pathways. Changes in serum transaminases and proinflammatory cytokines expression showed that Cd could induce acute hepatotoxicity. Moreover, Nrf2 and its downstream heme oxygenase 1 (HO-1) were inhibited by Cd exposure, and Kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2, was increased. Furthermore, NF-κB, NLRP3, and MAPKs signaling pathways were all activated by Cd intoxication. In conclusion, the inhibition of Nrf2, HO-1, and the activation of NF-κB, NLRP3, and MAPKs all contribute to Cd-induced liver injury.Keywords:Cadmium;acute liver injury;Nrf2;NLRP3;NF-κB;MAPKs
研究领域:
毒理学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2023
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IF 3.3
Miao Xing,Xiaoyu Ma,Xi Wang,Haoze Wang,Minjuan Xie,Ziwen Zhang,Jie Zhou
Emodin has been demonstrated to possess multiple pharmacological activities. However, emodin has also been reported to induce nephrotoxicity at high doses and with long-term use, and the underlying mechanism has not been fully disclosed. The current study aimed to investigate the roles of oxidative stress and ferroptosis in emodin-induced kidney toxicity. Mice were intraperitoneally treated with emodin, and NRK-52E cells were exposed to emodin in the presence or absence of treatment with Jagged1, SC79, or t-BHQ. Emodin significantly upregulated the levels of blood urea nitrogen, serum creatinine, malondialdehyde, and Fe 2+ , reduced the levels of superoxide dismutase and glutathione, and induced pathological changes in the kidneys in vivo. Moreover, the viability of NRK-52E cells treated with emodin was reduced, and emodin induced iron accumulation, excessive reactive oxygen species production, and lipid peroxidation and depolarized the mitochondrial membrane potential ( ΔΨm ). In addition, emodin treatment downregulated the activity of neurogenic locus notch homolog protein 1 (Notch1), reduced the nuclear translocation of nuclear factor erythroid-2 related factor 2 (Nrf2), and decreased glutathione peroxidase 4 protein levels. However, Notch1 activation by Jagged1 pretreatment, Akt activation by SC79 pretreatment, or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of emodin in NRK-52E cells. Taken together, these results revealed that emodin-induced ferroptosis triggered kidney toxicity through inhibition of the Notch1/Nrf2/glutathione peroxidase 4 axis.
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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肾脏生理学
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DOI
PubMed
高影响因子
Journal of Cancer
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2022
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IF 4.478
Kezhong Tang,Qing Chen,Yanmo Liu,Lantian Wang,Wenjie Lu
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo . Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.
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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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Yan-Ling Qian,Bang-Yin Tan,Shi-Shi Qin,Xian-Run Wu,Zhuo-Qi Shi,Yun-Li Zhao,Xiao-Dong Luo
Ethnopharmacological relevance Crotalari a assamica Benth, one of the folk medicinal plants in the "Dai" of China, is commonly used to treat liver and bile related diseases. However, its bioactive compounds and the mechanism related to traditional use remain unclear. Aim of the study To investigate the protective compounds and mechanism of C . assamica on drug-induced liver injury. Materials and methods The acetaminophen (APAP)-induced mice and cell model were carried out to reveal the liver protection of the extract of C . assamica (ECA) and bioactive compounds in vitro and in vivo . The protective pathway was explored using transcriptome analysis, and binding targets were predicted by structure-based binding prediction and dynamic simulation, which were further supported by qPCR and Western Blot experiments on the livers of treated mice. Results ECA reduced the contents of serum lactate dehydrogenase, aspartate transaminase, and alanine transaminase significantly, adjusted the oxidative indices of serum and liver tissues, and ameliorated inflammation and necrosis of liver tissues, as well as up-regulated expressions of NQO1, HO-1, Nrf2, p-AKT, BCL-2, AKT, and IL-6 in vivo . Moreover, its bioactive compound sarosiensin V increased the viability of APAP-induced HepG2 cells, and restored liver function activity, accompanied by enhanced antioxidation and mitochondrial membrane potential significantly. Conclusion C. assamica and its bioactive compound sarosiensin V inhibited oxidative stress, inflammation, apoptosis and necrosis of liver tissues, which was associated with the upregulation of the Nrf2 pathway, and then supporting its traditional use for liver protection.
研究领域:
药理学
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肝脏病学
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分子生物学
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天然产物化学
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氧化应激
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药物代谢
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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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
PHYTOMEDICINE
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2023
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IF 7.9
Yong Fang Gong,Shu Hou,Jia-Cheng Xu,Yan Chen,Le-Le Zhu,Ying-Ying Xu,Yu-Qing Chen,Miao-Miao Li,Li-Li Li,Jing-Jing Yang,Yan Yang
Background Phosphorylated Smad3 isoforms are reversible and antagonistic, and the tumour-suppressive pSmad3C can shift to an oncogenic pSmad3L signal. In addition, Nrf2 has a two-way regulatory effect on tumours, protecting normal cells from carcinogens and promoting tumour cell survival in chemotherapeutics. Accordingly, we hypothesised that the transformation of pSmad3C/3L is the basis for Nrf2 to produce both pro- and/or anti-tumourigenic effects in hepatocarcinogenesis . Astragaloside IV (AS-IV), the major component of Astragalus membranaceus , exerts anti-fibrogenic and carcinogenic actions. Lately, AS-IV administration could delay the occurrence of primary liver cancer by persistently inhibiting the fibrogenesis and regulating pSmad3C/3 L and Nrf2/HO-1 pathways synchronously. However, effect of AS-IV on hepatocarcinogenesis implicated in the bidirectional cross-talking of pSmad3C/3 L and Nrf2/HO-1 signalling, especially which one contributes palpably than the other still remains unclear. Purpose This study aims to settle the above questions by using in vivo (pSmad3C +/− and Nrf2 −/− mice) and in vitro (plasmid- or lentivirus- transfected HepG2 cells) models of HCC . Study design and methods The correlation of Nrf2 to pSmad3C/pSmad3L in HepG2 cells was analysed by Co-immunoprecipitation and dual-luciferase reporter assay. Pathological changes of Nrf2, pSmad3C, and pSmad3L in human HCC patients, pSmad3C +/- mice, and Nrf2 −/- mice were gauged by immunohistochemical, haematoxylin and eosin staining, Masson, and immunofluorescence assays. Finally, western blot and qPCR were used to verify the bidirectional cross-talking of pSmad3C/3L and Nrf2/HO-1 signalling protein and mRNA in vivo and in vitro models of HCC. Results Histopathological manifestations and biochemical indicators revealed that pSmad3C +/- could abate the ameliorative effects of AS-IV on fibrogenic/carcinogenic mice with Nrf2/HO-1 deactivation and pSmad3C/p21 transform to pSmad3L/PAI-1//c-Myc. As expected, cell experiments confirmed that upregulating pSmad3C boosts the inhibitory activity of AS-IV on phenotypes (cell proliferation, migration and invasion), followed by a shift of pSmad3L to pSmad3C and activation of Nrf2/HO-1. Synchronously, experiments in Nrf2 −/- mice and lentivirus-carried Nrf2shRNA cell echoed the results of pSmad3C knockdown. Complementarily, Nrf2 overexpression resulted in the opposite result. Furthermore, Nrf2/HO-1 contributes to AS-IV's anti-HCC effect palpably compared with pSmad3C/3L. Conclusion These studies highlight that harnessing the bidirectional crosstalk pSmad3C/3 L and Nrf2/HO-1, especially Nrf2/HO-1 signalling, acts more effectively in AS-IV's anti-hepatocarcinogenesis, which may provide an important theoretical foundation for the use of AS-IV against HCC.
研究领域:
分子生物学
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癌症研究
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Pharmacology Research & Perspectives
·
2025
·Vol. 13
·期 3
·e70094
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IF 2.3
Lei Zhu,Mengru Ding,Lina Liu,Pingchuan Yuan,Taili Shao,Chunyan Liu,Chuanhu Xi,Jun Han,Yuyan Zhou,Donglin Zhang,Guodong Wang
Diabetic nephropathy (DN) is a common complication of diabetes mellitus, with oxidative stress playing a critical role in its development. Burdock fructooligosaccharide (BFO), a major compound in Burdock, exhibits antioxidative effects. However, its mechanisms of action and effects on diabetic nephropathy are not clear enough. This study aims to explore the mechanisms of BFO and its impact on streptozotocin-induced diabetic nephropathy in mice. Male C57BL/6J mice were randomly divided into normal control, DN, and BFO groups. Relevant serum biochemical parameters were detected using kits. Renal injury was evaluated through fluorescence microscopy, histopathology, and transmission electron microscopy. Nrf2/HO-1 signaling was analyzed via quantitative real-time PCR, western blotting, and immunohistochemistry. In DN mice, BFO significantly reduced fasting blood glucose, kidney index, urine protein, serum creatinine, blood urea nitrogen, total cholesterol, triglyceride, and low-density lipoprotein cholesterol, while significantly increasing high-density lipoprotein, SOD, and CAT levels. Additionally, BFO protected against streptozotocin-induced renal injury, restored podocyte function, increased both mRNA and protein expression of Nrf2, HO-1, and Bcl-2, and decreased those of Bax. In conclusion, BFO can be used to treat streptozotocin-induced renal injury in mice and is a promising candidate for diabetic nephropathy treatment.
研究领域:
药理学
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分子生物学
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糖尿病研究
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DOI
PubMed
高影响因子
Antioxidants
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2025
·Vol. 14
·期 5
·576
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IF 6.6
Jiaming Chen,Yuting Fu,Shaoping Weng,Jianguo He,Chuanfu Dong
Scale drop disease virus (SDDV) poses an escalating threat to global aquaculture, prompting an urgent need for research. Our study found that SDDV infection upregulates genes related to iron, oxidative stress, and lipid metabolism, causing iron overload, reactive oxygen species (ROS) accumulation, and ultimately ferroptosis. Among the tested antioxidants, vitamin C (VC) demonstrated the most potent inhibitory effect in mandarin fish, reducing SDDV-induced mortality by 37.5%. qPCR and IFA results showed that VC effectively suppressed SDDV infection; decreased ROS, lipid peroxidation (LPO), and iron levels; and enhanced glutathione peroxidase 4 (GPX4) expression in infected cells. Mechanistically, VC’s inhibitory effect was reversed by the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML-385, indicating an Nrf2-dependent pathway. VC promoted Nrf2 nuclear translocation and activated downstream antioxidant genes. Moreover, VC modulated inflammation by regulating pro- and anti-inflammatory factors. These findings suggest VC as a promising therapeutic for SDDV infection.
研究领域:
水产养殖学
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病毒学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2021
·
IF 3.503
Jiaqi Lu,Lili Gu,Qin Li,Ningzi Wu,Hongxing Li,Xinyue Zhang
Context Andrographolide (Andro) has a neuroprotective effect and a potential for treating Alzheimer’s disease (AD), but the mechanism has not been elucidated.Objective The efficacy of Andro on p62-mediated Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathways in the aluminium maltolate (Al(mal)3)-induced neurotoxicity in PC12 cell was explored.Materials and methods PC12 cells were induced by Al(mal)3 (700 μM) to establish a neurotoxicity model. Following Andro (1.25, 2.5, 5, 10, 20, 40 μM) co-treatment with Al(Mal)3, cell viability was detected with MTT, protein expression levels of β-amyloid precursor protein (APP), β-site APP cleaving enzyme 1 (BACE1), Tau, Nrf2, Keap1, p62 and LC3 were measured via western blotting or immunofluorescence analyses. Nrf2, Keap1, p62 and LC3 mRNA, were detected by reverse transcription-quantitative PCR.Results Compared with the 700 μM Al(mal)3 group, Andro (5, 10 μM) significantly increased Al(mal)3-induced cell viability from 67.4% to 91.9% and 91.2%, respectively, and decreased the expression of APP, BACE1 and Keap1 proteins and the ratio of P-Tau to Tau (from 2.75- fold to 1.94- and 1.70-fold, 2.12-fold to 1.77- and 1.56-fold, 0.68-fold to 0.51- and 0.55-fold, 1.45-fold to 0.82- and 0.91-fold, respectively), increased the protein expression of Nrf2, p62 and the ratio of LC3-II/LC3-I (from 0.67-fold to 0.93- and 0.94-fold, 0.64-fold to 0.88- and 0.87-fold, 0.51-fold to 0.63- and 0.79-fold, respectively), as well as the mRNA expression of Nrf2, p62 and LC3 (from 0.48-fold to 0.92-fold, 0.49-fold to 0.92-fold, 0.25-fold to 0.38-fold). Furthermore, Nrf2 and p62 nuclear translocation were increased and keap1 in the cytoplasm was decreased in the presence of Andro. Silencing p62 or Nrf2 can significantly reduce the protein and mRNA expression of Nrf2 and p62 under co-treatment with Andro and Al(mal)3.Discussion and conclusions Our results suggested that Andro could be a promising therapeutic lead against Al-induced neurotoxicity by regulating p62-mediated keap1-Nrf2 pathways.
研究领域:
神经科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Jiaxin Li,Hengju Ge,Yang Xu,Jiahong Xie,Fujie Yan,Wei Chen
Geniposide (GEN), a main compound extracted from Gardenia jasminoides fruit, has various biological activities including anti-inflammation, cellular damage alleviation, neuroprotection, and others. However, the effect of GEN on oxidative stress in hepatic cells is yet to be investigated. Our study uncovered that GEN eliminated excess intracellular free radicals by activating the Nrf2/ARE signaling pathway in H2O2-treated hepatocytes, while the protective effect was blocked by ML385 (an inhibitor of Nrf2). Moreover, H2O2 led to upregulation of miR-27b-3p in L02 cells, which was restrained by GEN. Overexpression of miR-27b-3p greatly weakened the antioxidant capacity of GEN in hepatocytes via directly targeting the Nrf2 gene. Our findings indicated that GEN treatment recovered H2O2-induced oxidative stress via targeting miR-27b-3p and thereby enhanced the antioxidant capacity by stimulating nuclear translocation and accumulation of Nrf2. These findings suggest that inhibition of miR-27b-3p to activate the Nrf2/ARE pathway by GEN is a potential alternative for hepatic oxidative damage alleviation.
研究领域:
药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Chengji Dong,Gaoxiang Yu,Xianhui Ma,Zhuliu Chen,Ningning Yang,Xuankuai Chen,Yingying Lai,Jiayi Zhao,Yanlan Gu,Kailiang Zhou,Weiyang Gao,Jian Ding,Xuwei Zhu
Background How to improve flap necrosis in distal flaps is still a popular topic in clinical flap research. Zingerone (ZIN), as a plant extract, has therapeutic effects on many diseases. The purpose of our study was to explore whether ZIN can promote the survival of ischaemic skin flaps and its specific mechanism. Methods An ischemic flap model was established in the dorsal region of mice. The changes of angiogenesis, oxidative stress, apoptosis and Keap1-Nrf2 related proteins in the skin flap were detected by immunofluorescence, western blot and qPCR. Overexpression of Keap1 by adeno-associated virus (AAV) was used to study the specific pathway and mechanism. Results The results showed that ZIN can induce angiogenesis and reduce oxidative stress and apoptosis to promote flap survival. Increased expression of Keap1 reversed the therapeutic effect of ZIN. Conclusion ZIN activates Nrf2 by inhibiting Keap1 activation, thus promoting angiogenesis and inhibiting oxidative stress and apoptosis.
研究领域:
外科手术
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药理学
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分子生物学
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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）