American Journal of Translational Research
·
2017
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IF 2.829
Yuanfeng Zhu,Shijun Fan,Ning Wang,Xiaoli Chen,Yongjun Yang,Yongling Lu,Qian Chen,Jiang Zheng,Xin Liu
Activation of NADPH oxidase 2 (NOX2) triggers reactive oxygen species (ROS) generation, both of which are essential for robust microbial clearance by phagocytes. However, it is unknown whether inhibition of NOX2 activation or ROS generation affects cellular phagocytosis. Here, we found that the classic NOX2 inhibitor diphenyleneiodonium (DPI) induced uptake of E. coli by murine peritoneal macrophages through enhancing phagocytosis, and this effect was temperature-sensitive and attenuated by cytochalasin D as well as chemical inhibition of Syk and PLCγ, two downstream kinases involved in actin polymerization during phagocytosis. DPI also decreased the production of TNF-α and IL-6 resulting from E. coli stimulation. The DPI-induced enhancement of phagocytosis was independent of NOX2 inhibition or ROS generation but depended on increased intracellular calcium and activation of the p38 MAPK signaling pathway. Furthermore, DPI enhanced bacterial elimination and ameliorated inflammation in E. coli -infected mice, leading to improved survival. Our results demonstrate that DPI facilitates ROS-independent bacterial phagocytosis by macrophages through activation of calcium and p38 MAPK signaling pathways.
研究领域:
免疫学
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分子生物学
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医学
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DOI
PubMed
高影响因子
Plants-Basel
·
2022
·Vol. 11
·期 19
·2487
·
IF 4.658
Yifei Zhang,Yishan Sun,Weiqing Li,Jiayu Li,Rongqiong Xu,Jiarui Du,Zesong Li,Guibin Li,Kejun Yang
To explore the effects of iminodisuccinic acid (a chelating agent) on maize (Zea maysL.) seed germination under lead (Pb) stress, we comparatively analyzed the effects of applying different concentrations of iminodisuccinic acid (0, 5, 20, and 100 mmol·dm−3) and combined an addition of exogenous substances regulating reactive oxygen species production on maize seed germination, seedling growth, H2O2content, NADPH oxidase activity, and antioxidant enzyme activities under Pb-stressed and Pb-free conditions. Iminodisuccinic acid (100 mmol·dm−3) significantly delayed seed germination under normal germination conditions and alleviated the inhibitory effects of Pb stress (20 mmol·dm−3) on seed germination. Under normal conditions (without Pb stress), the iminodisuccinic acid-induced inhibition of seed germination was enhanced by treatment with dimethylthiourea (a specific scavenger of reactive oxygen species) or diphenyleneiodonium chloride (a specific inhibitor of NADPH oxidase), but diminished by treatment with H2O2, CaCl2, diethyldithiocarbamic acid (a specific inhibitor of superoxide dismutase), or aminotriazole (a specific inhibitor of catalase). Under Pb stress, iminodisuccinic acid partially eliminated the excessive H2O2accumulation, improved superoxide dismutase and catalase activity, and weakened the high NADPH oxidase activity. In addition, Ca2+chelation may be essential for maintaining the reactive oxygen species’ balance and improving seed germination and seedling growth by iminodisuccinic acid supplementation in maize under Pb stress. The proposed iminodisuccinic acid supplementation-based method improved maize seed germination in Pb-polluted soil.Keywords:maize;chelator;lead stress;ROS;hydrogen peroxide;NADPH oxidase;seed germination
研究领域:
植物学
·
环境科学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2019
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IF 3.17
Jiamao Lin,Lijun Fang,Hui Li,Zhenxiang Li,Linmao Lyu,Haiyong Wang,Jun Xiao
Doxorubicin (DOX) is a classic anti-tumor chemotherapeutic used to treat a wide range of tumors. One major downfall of DOX treatment is it can induce fatal cardiotoxicity. Astragaloside IV (AS-IV) is one of the primary active ingredients that can be isolated from the traditional Chinese herbal medicine, Astragalus membranaceus . This study uses both in vitro and in vivo tools to investigate whether AS-IV alleviates DOX induced cardiomyopathy . We found that AS-IV supplementation alleviates body weight loss, myocardial injury , apoptosis of cardiomyocytes, cardiac fibrosis and cardiac dysfunction in DOX-treated mice. Also, DOX-induced cardiomyocyte injury and apoptosis were effectively improved by AS-IV treatment in vitro . NADPH oxidase (NOX) plays an important role in the progress of the oxidative signal transduction and DOX-induced cardiomyopathy. In this study, we found that AS-IV treatment relieves DOX-induced NOX2 and NOX4 expression and oxidative stress in cardiomyocytes. In conclusion, AS-IV, an antioxidant, attenuates DOX-induced cardiomyopathy through the suppression of NOX2 and NOX4.
研究领域:
药理学
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心脏病学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
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2018
·
IF 7.126
Dong Hou,Zhaojian Liu,Xiuhua Xu,Qiao Liu,Xiyu Zhang,Beihua Kong,Jian-Jun Wei,Yaoqin Gong,Changshun Shao
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS). Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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DOI
PubMed
高影响因子
JOURNAL OF PLANT PHYSIOLOGY
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2023
·
IF 4.3
Lin Xiao,Wenna Ma,Jiarong Zhang,Xiaojun Pu,Zed Rengel,Zhongbang Song,Qi Chen
Flavonols are well-known antioxidants that prevent stomatal closure via interfering with ROS signaling. Phytomelatonin regulates stomatal closure, but the signaling pathways are still largely unknown. Here, we investigated the role of flavonols in phytomelatonin-mediated stomatal closure in tobacco plants. The application of melatonin induced stomatal closure through NADPH oxidase-mediated ROS production. Transgenic tobacco plants overexpressing soybean GmSNAT1 (coding for serotonin N -acetyltransferase that catalyzes the penultimate step in phytomelatonin biosynthesis) had higher phytomelatonin concentration, accumulated more ROS in guard cells and were more sensitive to melatonin-induced stomatal closure than the wild-type plants, which was associated with the higher expression of PMTR1 -homologous genes. Exogenous melatonin decreased flavonol concentrations in guard cells and the expression of flavonoid-related genes in wild-type and transgenic tobacco plants, and these inhibitory effects were more obvious in GmSNAT1 -overexpressing plants than the wild type. However, the melatonin-mediated stomatal closure and ROS production were diminished by the application of kaempferol (a type of flavonol). Additionally, transgenic tobacco plants with increased expression of NtFLS (encoding flavonol synthase) were less sensitive to melatonin-induced stomatal closure. In conclusion, phytomelatonin hampers the biosynthesis of flavonols in guard cells, which results in high concentration of ROS and induces stomatal closure in tobacco plants.
研究领域:
植物生理学
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分子生物学
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植物生物化学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2022
·
IF 5.572
Xiangyuan Liu,Li Song
Epidemiologic studies have revealed that Dichlorodiphenyltrichloroethane (DDT) and its metabolites are associated with liver diseases. However, there has been little emphasis on the mechanism underlying liver toxicity of o,p’- DDT and relevant effective inhibitors investigation. This study indicated o,p’- DDT exposure significantly decreased cell viability and promoted lactate dehydrogenase (LDH) release based on the investigation of cytotoxicity by trypan blue exclusion counts, MTT, and lactate dehydrogenase (LDH) assays. Comet, micronuclei, and DNA-protein crosslinks (DPC) assays demonstrated o,p’- DDT exposure increased the comet parameters, micronuclei frequency, and DPC coefficient. Meanwhile, we found o,p’- DDT induced mitochondria-dependent apoptosis , which is characterized by the loss of mitochondrial membrane potential (Δψm), decreased Bcl-2 expression, and increased protein levels of Bax, cytochrome c , activated-caspase-9, and activated-caspase-3. Furthermore, o,p’- DDT induced reactive oxygen species (ROS) overproduction, decreased the protein levels of nuclear factor erythroid-derived 2-like 2 (Nrf2) in the nuclear, and enhanced the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase . However, quercetin treatment significantly antagonized o,p’- DDT-induced cytotoxicity, genotoxicity , and apoptosis as well as effects on ROS, Nrf2, and NADPH oxidase. Taken together, these findings suggested quercetin could alleviate o,p’- DDT-induced toxicity in HL-7702 cells via inhibiting ROS production, which is modulated by down-regulating nuclear Nrf2 levels and NADPH oxidase expression.
研究领域:
毒理学
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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
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Yuqian Li,Lijingzhe Hou,Kang Cheng,Guangbo He,Jau-Shyong Hong,Sheng Li,Jie Zhao,Yanjie Guo
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory condition of the gastrointestinal tract with limited treatment options and no definitive cure. Emerging evidence implicates NADPH oxidase (Nox) in IBD pathogenesis, but the specific subtype involved and its therapeutic potential remain unclear. To assess the efficacy of dextromethorphan (DM), a potent Nox2 inhibitor, we employed a dextran sulfate sodium (DSS)-induced chronic colitis model in mice. Mice exposed to intermittent DSS for 34 days developed IBD-like symptoms, including weight loss, elevated disease activity index (DAI), colon shortening, and epithelial barrier disruption. DM exhibited a bimodal protective effect: both standard-dose DM (10 mg/kg/day) and ultralow-dose DM (ULDM, 10 ng/kg/day) significantly reduced colitis severity, with ULDM proving more effective and selected for further studies. Notably, ULDM remained effective when post-administered after DSS exposure. Histological analyses revealed that ULDM reduced immune cell infiltration, crypt damage, and tissue disruption. It also suppressed pro-inflammatory cytokine expression (MCP-1, IL-6, IL-1β, TNF-α) and oxidative stress markers (myeloperoxidase, malondialdehyde, 8-hydroxydeoxyguanosine), while enhancing anti-inflammatory cytokines (IL-4, IL-10) and antioxidant enzymes (catalase, superoxide dismutase). Importantly, ULDM protected Nox1 KO but not Nox2 KO mice, indicating a Nox2-dependent mechanism. In vitro, ULDM inhibited Nox2 activation in primary macrophages and RAW 264.7 cells by blocking the membrane translocation of p47 phox . Furthermore, our study suggested a feed-forward inflammatory cycle between epithelial cell death and macrophage overactivation that exacerbated colitis. Together, these findings demonstrated that Nox2 played a central role in DSS-induced chronic colitis and identified ultralow-dose dextromethorphan as a promising, mechanism-based therapeutic candidate for IBD.
研究领域:
免疫学
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药理学
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胃肠病学
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分子生物学
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炎症性肠病研究
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Ying Huang,Huisi Zhao,Yu Zhang,Chuanqi Zhao,Jinsong Ren,Xiaogang Qu
The nanozyme with NADPH oxidase (NOX)-like activity can promote the consumption of NADPH and the generation of free radicals. In consideration of that the upregulation of glucose-6-phosphate dehydrogenase (G6PD) would accelerate the compensation production of NADPH, for inhibition of G6PD activity, our designed bioorthogonal nanozyme can in situ catalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone (DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined platform can disrupt NADPH homeostasis, leading to the collapse of the antioxidant defense system in the tumor cells. The enzyme-like activity of PdCuFe is further enhanced when irradiated by NIR-II light. The destruction of NADPH homeostasis can promote ferroptosis and, in turn, facilitate mild photothermal therapy. Our design can realize NADPH depletion and greatly improve the therapeutic effect through metabolic regulation, which may provide inspiration for the design of bioorthogonal catalysis
研究领域:
癌症治疗
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生物医学工程
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纳米技术
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生物化学
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诊疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF HISTOCHEMISTRY
·
2023
·
IF 2
Qian Hu,Ran Tao,Xiaoyun Hu,Haibo Wu,Jianjun Xu
Acute pancreatitis is an inflammatory response in the pancreas, involving activation of pancreatic enzymes. Severe acute pancreatitis (SAP) often causes systemic complications that affect distant organs, including the lungs. The aim of this study was to explore the therapeutic potential of piperlonguminine on SAP-induced lung injury in rat models. Acute pancreatitis was induced in rats by repetitive injections with 4% sodium taurocholate. Histological examination and biochemical assays were used to assess the severity of lung injury, including tissue damage, and levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), reactive oxygen species (ROS), and inflammatory cytokines. We found that piperlonguminine significantly ameliorated pulmonary architectural distortion, hemorrhage, interstitial edema, and alveolar thickening in rats with SAP. In addition, NOX2, NOX4, ROS, and inflammatory cytokine levels in pulmonary tissues were notably decreased in piperlonguminine- treated rats. Piperlonguminine also attenuated the expression levels of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB). Together, our findings demonstrate for the first time that piperlonguminine can ameliorate acute pancreatitis-induced lung injury via inhibitory modulation of inflammatory responses by suppression of the TLR4/NF-κB signaling pathway.
研究领域:
药理学
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炎症
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肺医学
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胃肠病学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2021
·
IF 6.025
Bangrong Cai,Mengya Liu,Jinxing Li,Dujuan Xu,Jiansheng Li
Chronic obstructive pulmonary disease (COPD) is widely recognized as a global public health problem and the third leading cause of mortality worldwide by 2020. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual-specificity protein and lipid phosphatase that plays an important role in COPD. However, the redox regulation of PTEN in the development of COPD was poorly studied. Our results showed that cigarette smoke extract (CSE) could oxidize PTEN in a time-dependent manner in BEAS-2B cells, whereas PTEN oxidation exposed to CSE was delayed compared to that of H 2 O 2. Additionally, we found that ROS derived from DUOX1 and 2 of NADPH oxidases were mainly responsible for oxidative inactivation PTEN, also simultaneously led to Trx-1 inactivation by dimerization . Oxidative mechanism of PTEN exposed to CSE was mediated by forming a disulfide bond between Cys 71 and Cys 124 , similar to H 2 O 2 . Inactivation of PTEN resulted in the increased phosphorylation of Akt. In conclusion, CSE exposure could elevate the intracellular ROS mainly from DUOX1 and 2 to oxidize PTEN and Trx-1 resulting in Akt activation, eventually cause the occurrence of COPD, suggesting that PTEN is a potential target for new therapies in COPD.
研究领域:
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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氧化应激
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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
Meiqi Wang,Beixuan Yang,Xin Li,Huanhuan Ma,Xia Ou,Zeren Dawa,Fangle Liu,Chenchen Zhu,Chaozhan Lin
Background Nonalcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of fat in the liver, has emerged as a leading cause of chronic liver diseases and malignancies. However, there remains a scarcity of approved therapeutic interventions. Brunodelphinine A (BruA) is a diterpenoid alkaloid isolated from Delphinium brunonianum Royle. in our previous study. It was evaluated with strong activity of lipid-lowering. Nevertheless, its precise effects and mechanisms in the treatment of NAFLD remain unexplored. Purpose The present study aims to elucidate the effects of BruA against NAFLD and to investigate its potential pharmacological mechanism. Methods The lipid-lowering and anti-NAFLD effects of BruA were evaluated in the free fatty acid (FFA)-induced cell model and high-fat diet (HFD)-induced mice. Network pharology analysis combined with Non-targeted metabolomics study was used to explore the key mechanism of BruA. Furthermore, molecular docking and cellular thermal shift assay (CETSA) were used to simulate and verify the targeting activation of BruA on the NADPH oxidase 4 (NOX4). The core role of NOX4 in BruA in regulating nicotinamide adenine dinucleotide (NAD + )/Sirtuin 1 (SIRT1) and peroxisome proliferators-activated receptors (PPARs) signaling pathway to improve oxidative stress and lipid metabolic disorders was further focused, and such mechanism was evaluated in WT and NOX4 knockout mice or HepG2 cells. Results BruA dose-dependently reduced FFA-induced lipid accumulation and cell damage in vitro , and mitigated HFD-induced NAFLD in mice. At the metabolite level, BruA improved metabolic disorder in NAFLD mice focusing on the metabolism of arachidonic acid and linolenic acid, which has been considered as signs of oxidative stress, that positively correlated with NAFLD. BruA targeting inhibited NOX4 to mitigate reactive oxygen species (ROS)-mediated oxidative stress and prevent abnormal redox levels, thereby regulating NAD + /SIRT1 in protecting the liver from oxidative damage, and further affected downstream PPARs-related lipid metabolism regulation processes, thus alleviating hepatic lipid accumulation. Furthermore, NOX4 deficiency suppressed the protective effect of BruA in vitro and in vivo . Conclusion BruA improved oxidative stress and lipid metabolic disorders of NAFLD by regulating the NOX4-SIRT1-PPARs signaling axis in vivo and in vitro , and this regulation is targeting dependent on NOX4. For its mechanisms of antioxidant stress and lipid-lowering, there is great therapeutic potential for BruA in the treatment of period with elevated lipids and inflammation production in NAFLD.
研究领域:
药理学
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生物化学
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分子生物学
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药物化学
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细胞生物学
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代谢组学
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药物研发
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肝病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 11
·4962-4973
·
IF 5.31
Mingyu He,Gege Yan,Yang Wang,Rui Gong,Hong Lei,Shuting Yu,Xiaoqi He,Guanghui Li,Weijie Du,Tianshuai Ma,Manqi Gao,Meixi Yu,Shenzhen Liu,Zihang Xu,Elina Idiiatullina,Naufal Zagidullin,Valentin Pavlov,Benzhi Cai,Ye Yuan,Lei Yang
Osteosarcoma (OS) is the most common primary malignant bone tumour in adolescence. Lately, light-emitting diodes (LED)-based therapy has emerged as a new promising approach for several diseases. However, it remains unknown in human OS. Here, we found that the blue LED irradiation significantly suppressed the proliferation, migration and invasion of human OS cells, while we observed blue LED irradiation increased ROS production through increased NADPH oxidase enzymes NOX2 and NOX4, as well as decreased Catalase (CAT) expression levels. Furthermore, we revealed blue LED irradiation-induced autophagy characterized by alterations in autophagy protein markers including Beclin-1, LC3-II/LC3-I and P62. Moreover, we demonstrated an enhanced autophagic flux. The blockage of autophagy displayed a remarkable attenuation of anti-tumour activities of blue LED irradiation. Next, ROS scavenger N-acetyl-L-cysteine (NAC) and NOX inhibitor diphenyleneiodonium (DPI) blocked suppression of OS cell growth, indicating that ROS accumulation might play an essential role in blue LED-induced autophagic OS cell death. Additionally, we observed blue LED irradiation decreased EGFR activation (phosphorylation), which in turn led to Beclin-1 release and subsequent autophagy activation in OS cells. Analysis of EGFR colocalization with Beclin-1 and EGFR-immunoprecipitation (IP) assay further revealed the decreased interaction of EGFR and Beclin-1 upon blue LED irradiation in OS cells. In addition, Beclin-1 down-regulation abolished the effects of blue LED irradiation on OS cells. Collectively, we concluded that blue LED irradiation exhibited anti-tumour effects on OS by triggering ROS and EGFR/Beclin-1-mediated autophagy signalling pathway, representing a potential approach for human OS treatment.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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光生物学
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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）