ACS Omega
·
2024
·
IF 3.7
Chenxin Xu,Yinghua Chen,Zhuoen Zhou,Ying Yan,Wenying Fu,Peng Zou,Daoyong Ni
Lung cancer is one of the leading causes of death. Celastrol is a natural product that has shown anticancer activity but has not yet been applied in clinical settings due to its narrow therapeutic window. In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol. At the same time, celastrol upregulated the expression of cytoprotective transcription factor Nrf2 and its downstream proteins, which are effective in preventing the oxidative damage caused by ROS accumulation. Notably, we found that the overexpression of Nrf2 enhances the tolerance of lung cancer cells to celastrol and that lung cancer cells H460 with a Keap1 mutation are insensitive to celastrol. This indicates that the increase in Nrf2 contributes to the survival of lung cancer cells. Thus, we brought in an Nrf2 inhibitor ML385 to suppress the activation of Nrf2. We found that when ML385 and celastrol were added together the survival rates of lung cancer cells decreased more and the detected ROS level became much higher compared to treatment with celastrol alone. We also discovered that ML385 suppressed the expression of HO-1 and GCLC, which amplified celastrol-induced ATF4/CHOP-dependent endoplasmic reticulum stress (ER stress). Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.
研究领域:
肿瘤学
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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 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
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Tianfeng Yang,Suyu Zhang,Kun Nie,Xiuhong Peng,Jian Huo,Xiao Fu,Yanmin Zhang
Although ferroptosis as an emerging way exhibits tremendous promising in the therapy of hepatocellular carcinoma (HCC), the novel therapeutic agents targeting ferroptosis are still scarce. In our previous study, we found that the natural products toosendanin (TSN) possessed significant anti-proliferative efficacy by regulating WW domain-containing oxidoreductase (WWOX) in HCC. However, there is very limited understanding about TSN-induced ferroptosis, and the role of WWOX in ferroptosis has not been studied. In present study, we investigated the effect and underlying molecular mechanisms of TSN in WWOX-mediated ferroptosis in HCC. We found that TSN induced ferroptosis in HCC cells and its effect was dependent on WWOX. RNA-seq and RT-qPCR assay identified that TSN significantly increased spermidine/spermine N1-acetyltransferase 1 (SAT1) expression while decreased solute carrier family 40 member 1 (SLC40A1) expression, which play vital roles in ferrous ion transport. Further dual-luciferase reporter assay and Co-IP assay revealed that TSN-induced WWOX activation controlled the transcriptional activity of p53 and NF-E2-related factor 2 (NRF2) by regulating their interaction. Meanwhile, IF assay and WB assay confirmed that TSN increased the nuclear distribution of p-WWOX and p-p53 dimers, but impeded the nuclear translocation of NRF2 by inducing its ubiquitination degradation, ultimately regulating the transcription of their downstream target genes. In addition, the results from cell viability assay and the tumor xenograft model verified that co-treatment of TSN, ML385 (NRF2 inhibitor), and MIRA-1 (p53 activator) could effectively inhibit HCC cells growth in the presence of Fer-1 (ferroptosis inhibitor) in vitro and in vivo. Overall, our study contributes to the necessary understanding of the molecular mechanisms of WWOX-mediated ferroptosis regulation, and identifies TSN as a potential therapeutic agent targeting ferroptosis for HCC.
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
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Wenjie Chen,Li Xie,Can Lv,Erqun Song,Xiaokang Zhu,Yang Song
Ferroptosis, an iron-dependent cell death driven by the lethal levels of lipid peroxidation (LPO), becomes a promising anticancer strategy. However, the anticancer efficacy of ferroptosis is often hindered by the activation of nuclear factor erythrocyte 2-associated factor 2 (Nrf2), which is an indispensable regulator of the cellular antioxidant balance by preventing the accumulation of intracellular reactive oxygen species (ROS). Herein, we present a rational design of a Tf-targeted cascade nanoplatform TPM@AM based on mesoporous polydopamine (MPDA) co-encapsulating a ferroptosis inducer (artesunate, ART) and an Nrf2-specific inhibitor (ML385) to enhance intracellular ROS and therefore amplify ferrotherapy. Transferrin (Tf) can specifically recognize the transferrin receptor (TfR) on the surface of the cell membrane, which binds and transports iron into cells. When TPM@AM is endocytosed, the high-acid tumor microenvironment and laser irradiation trigger the collapse of MPDA to release ART and ML385. Furthermore, MPDA endows the nanoplatform with photothermal capability. The nanoplatform exhibits high efficiency for synergistic tumor suppression, representing a spatiotemporal controllable therapeutic strategy for precise synergistic cancer therapy.
研究领域:
癌症生物学
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纳米技术
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治疗学
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药学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Deshan Yao,Bo Shi,Sichuan Wang,Liuxiang Bao,Meng Tan,Hui Shen,Zhengang Zhang,Xin Pan,Yi Yang,Yong Wu,Kaizheng Gong
Background Oxidative stress and inflammatory reaction play critical roles in acute myocardial infarction (AMI). Isoliquiritigenin (ISL), a flavonoid monomer extracted from licorice, has been found to have antioxidant and anti-inflammatory effects in cancer studies. Here, we tested the effect and underlying mechanisms of ISL on ischemia-induced myocardial injury in a mouse AMI model. Methods Adult C57BL/6 mice were pre-treated by intraperitoneal injection of ISL and/or a specific nuclear factor E2-related factor 2 (Nrf2) inhibitor ML385 for 3 days, respectively. Then, the AMI model was established by ligating the anterior descending branch of the left coronary artery. Myocardial oxidative stress status, inflammatory response, cardiac function and infarction size were assessed after 7th day of surgery. Results Compared with sham group, the reactive oxygen species (ROS) and malondialdehyde (MDA) level in AMI group were significantly increased. However, the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) level were dramatically decreased. ISL treatment significantly reduced the myocardial infarction area, improved cardiac function, inhibited the production of ROS and MDA and reduced the consumption of SOD and GSH-Px. Interestingly, ISL could significantly increase nuclear Nrf2 and cytosolic heme oxygenase 1 (HO-1) level in the infarcted myocardium and reduce the oxidative stress after AMI. Also, ISL treatment dramatically inhibited the activation of myocardial NF-κB pathway and reduced the expression of pro-inflammatory factors in the AMI group. However, the administration of ML385 not only suppressed the Nrf2/HO-1 activation, the anti-oxidant and anti-inflammatory effects induced by ISL, but also attenuated the beneficial role of ISL on reducing infarct size and improving cardiac function in the mouse with AMI. Conclusion The results suggested that activation of Nrf2/HO-1 pathway has an essential role in ISL-induced cardiac protection by alleviating myocardial oxidative stress and inflammation response in mice with AMI.
研究领域:
药理学
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心脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2019
·
IF 8.355
Haixia Liu,Qingzhu Yang,Wei Guo,Huiming Lin,Feng Zhang,Jingxiang Zhao,Tianyue Ma,Le Zhao,Na Xu,Ruiwen Wang,Jingyao Yu,Fengyu Qu
Although phototherapy has received widespread attention in recent years due to its high efficiency, low invasiveness, and minor side effects, there are still few studies on the relationship between phototherapy and immunotherapy. Therefore, non-stoichiometric CoWO 4-x nanoparticles (NPs) were strategically designed and prepared, as these can simultaneously generate hyperthermia and reactive oxygen species (ROS) under near-infrared laser irradiation, illustrating that they can be used to realize photothermal therapy (PTT) and photodynamic therapy (PDT) on tumors. CoWO 4-x NPs not only have strong near-infrared absorption, outstanding biocompatibility, and excellent photothermal stability but they also can be used as photoacoustic (PA) and Computer Tomography (CT) contrast agents for working with tumors. In particular, the relationships between phototherapy, immunogenic cell death (ICD) and immunoresistance are here discussed in depth, and enhanced phototherapy was achieved for the first time by injecting etoposide and ML385, which are two typical inhibitors for HSP60 and NRF2, respectively. Furthermore, the biocompatibility of materials in vivo was demonstrated through a variety of cell experiments, changes in mouse body weight, and histological analyses. Our work highlights the great potentials of non-stoichiometric CoWO 4-x NPs as a kind of multifunctional therapeutic agent for implementing enhanced phototherapy in breast cancer by reducing the immunoresistance of HSP60 and NRF2 toward PTT and PDT.
研究领域:
纳米技术
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癌症治疗
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免疫学
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生物医学工程
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Shu Long,Fu Hangjie,Pi Aiwen,Feng Yuliang,Dong Hui,Si Caijuan,Li Songtao,Zhu Feiye,Zheng Peifen,Zhu Qin
Ulcerative colitis (UC) is a recurring inflammatory bowel disease, in which oxidative stress plays a role in its progression, and regulation of the oxidative/antioxidative balance has been suggested as a potential target for the treatment of UC. The aim of this study was to evaluate the protective effect of andrographolide against UC and its potential antioxidant properties by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Dextran sulfate sodium (DSS) -induced UC mice and the LPS-induced HT29 inflammatory cell model were established to uncover the potential mechanisms of andrographolide. ML385, a Nrf2 inhibitor, was used in both models to assess whether andrographolide exerts a protective effect against UC through the Nrf2/HO-1 pathway. The in vivo experiment showed that andrographolide ameliorated the symptoms and histopathology of DSS-induced mice and restored the expressions of ZO-1, Occludin-1 and Claudin-1. Meanwhile, DSS-induced oxidative stress and inflammation were suppressed by andrographolide treatment, along with the upregulation of key proteins in the Nrf2/HO-1 pathway. In vitro experiments showed that andrographolide attenuated LPS-induced excessive generation of ROS in HT29 cells, reduced inflammatory factors, and upregulated the expression of proteins related to tight junctions and Nrf2/HO-1 pathway. In addition, ML385 abolished the beneficial effect of andrographolide. In conclusion, the protective effect of andrographolide against UC may involve the suppression of oxidative stress and inflammation via the Nrf2/HO-1 pathway.
研究领域:
药理学
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炎症性肠病
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yue Tang,Yueyue Kang,Xinru Zhang,Caiyi Cheng
Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a major factor in the pathogenesis of dry age-related macular degeneration (AMD). Although the therapeutic effect of mesenchymal stem cell (MSC) exosomes on dry AMD has been preliminarily discussed, the underlying mechanism has yet to be reported. Here, we demonstrate that MSC exosomes, acting as a nanodrug, can effectively reduce the incidence of dry AMD by regulating Nrf2/Keap1 signaling pathway. In the in vitro study, MSC exosomes relieved the damage of ARPE-19 cells, suppressed the activity of lactate dehydrogenase (LDH), decreased the level of reactive oxygen species (ROS) and upregulated the activity of superoxide dismutase (SOD). In the in vivo study, MSC exosomes were administered via intravitreal injection. MSC exosomes effectively protected RPE layer, photoreceptor outer segment/inner segment (OS/IS) layer and outer nuclear layer (ONL) from NaIO 3 -induced damage. Western blotting results showed that the ratio of Bcl-2/Bax was increased after pre-administration of MSC exosomes in both in vitro and in vivo studies. Moreover, MSC exosomes were found to upregulate the expressions of Nrf2, P-Nrf2, Keap1 and HO-1, while the antioxidant effect of MSC exosomes was blocked by ML385 (a Nrf2 inhibitor). Besides, immunofluorescence results showed that MSC exosomes upregulated the expression of P-Nrf2 in the nucleus compared to the oxidant group. These results indicate that MSC exosomes protect RPE cells from oxidative damage by regulating Nrf2/Kepa1 signaling pathway. In conclusion, MSC exosomes are promising nanotherapeutics for the treatment of dry AMD.
研究领域:
眼科学
·
干细胞生物学
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF SURGICAL RESEARCH
·
2022
·
IF 2.417
Ming Deng,Ping Xie,Junqi Liu,Yan Zhou,Zhonghui Chen,Yonggang Ma,Jianwei Yang
Introduction α-Cyperone has anti-inflammatory activities, but its effects on spinal cord injury (SCI) remain obscure. Thus, this study attempts to investigate the effects and modulatory mechanisms of α-Cyperone on SCI. Materials and methods An SCI model was established in rats which were further treated with α-Cyperone. Basso-Beattie-Bresnahan (BBB) scoring was used to assess motor rehabilitation of rats modeled with SCI. The spinal cord tissues were collected, and the effect of α-Cyperone on the histopathology of rats modeled with SCI was detected by hematoxylin-eosin staining. Rat primary cortical neuron was stimulated with H 2 O 2 and further treated with α-Cyperone and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. The levels of Nrf2, interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), Akt, toll-like receptor 4 (TLR4), and tumor necrosis factor-alpha (TNF-α) were detected by immunofluorescence staining and western blotting . Results α-Cyperone elevated the BBB score and ameliorated the damage of spinal cord tissue in rats modeled with SCI. The levels of IL-6, Nrf2, NF-κB, TLR4, and TNF-α were upregulated, whereas that of Akt was downregulated in rats and cells modeled with SCI. Furthermore, α-Cyperone diminished the levels of IL-6, NF-κB, TLR4, and TNF-α, while augmenting those of Nrf2 and Akt in rats and cells modeled with SCI. ML385 inhibited the Nrf2 level that had been promoted by α-Cyperone in the nucleus and elevated the Nrf2 level that had been suppressed by α-Cyperone in the cytosol of cells modeled with SCI. ML385 increased the levels of IL-6, NF-κB, TLR4, and TNF-α that had been inhibited by α-Cyperone and decreased the Akt level that had been enhanced by α-Cyperone in cells modeled with SCI. Conclusions α-Cyperone suppressed SCI-induced inflammation and spinal cord tissue damage via activating Akt/Nrf2 and suppressing NF-κB pathways.
研究领域:
神经科学
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药理学
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分子生物学
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病理学
✓ 已验证
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2025
·
IF 5.1
Zhida Long,Xiao Yu,Shijia Li,Nuo Cheng,Chenglong Huo,Xuewen Zhang,Shuai Wang
Introduction Oxidative stress is an important cause of acetaminophen (APAP)-induced liver injury (AILI). Sakuranetin (Sak) is an antitoxin from the cherry flavonoid plant with good antioxidant effects. However, whether sakuranetine has a protective effect on APAP-induced liver injury is not clear.Methods Mouse and HepG2 cell models of APAP injury were used to investigate the effect of sakuranetin on AILI and its mechanism. Serum transaminase levels, histological changes, inflammatory mediators, oxidative stress, ferroptosis-related markers and Nrf2 signaling pathway proteins were analyzed.Results Sakuranetin significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as inflammatory factor; increased HepG2 activity and decreased cell death; inhibited ROS production, increased glutathione (GSH) content, expression of Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), and decreased malondialdehyde and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) expression in mice and HepG2 cells after APAP treatment. Further analysis showed that sakuranetin induced the activation of the NFE2 Like BZIP Transcription Factor 2 (Nrf2) signaling pathway in liver tissue and HepG2 cells and promoted the nuclear translocation of Nrf2. Moreover, the hepatoprotective effect of sakuranetin and its inhibitory effect on ferroptosis were significantly attenuated by the Nrf2 inhibitor ML385.Conclusion Sakuranetin alleviates AILI by activating the Nrf2 signaling pathway and inhibiting ferroptosis, and sakuranetin may be a potential therapeutic agent for the treatment of AILI.
研究领域:
药理学
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毒理学
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肝病学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2026
·Vol. 15
·期 7
·888
·
IF 8.2
Yin Liu,Yan Wang,Xinyu Shi,Ruomei Che,Xiaoli He
Background:Danshen–Gegen is a classic herb pair in traditional Chinese medicine, which has been used to treat cardiovascular and cerebrovascular diseases. Ischemic stroke (IS) is a prevalent cerebrovascular condition; ferroptosis is one of the contributing factors driving the progression of IS. This study aims to determine the underlying mechanism and examine if Danshen–Gegen (DG) extract may prevent cerebral ischemia–reperfusion injury by preventing ferroptosis.Methods:The comprehensive compositional characterization of DG was analyzed by ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry (UPLC-Q-orbitrap MS). The experiments were conducted in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/re-oxygenation (OGD/R) cells. The neuroprotective effects of DG on IS were assessed by examining rat survival rates, infarct volume, behavioral scores, and cerebral water content. Then, we tested the accumulation of Fe2+and lipid peroxidation products such as reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and 4-hydroxynonenal (4-HNE) in rats and cells. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), Solute Carrier Family 7 Member 11 (-xCT), Glutathione peroxidase 4 (GPX4), Cyclooxygenase-2 (COX-2), Transferrin Receptor 1 (TFR1), and Long-chain-fatty-acid–CoA ligase 4 (ACSL4) was also assessed in vivo and in vitro.Results:UPLC-Q-orbitrap MS analysis was performed to characterize the chemical profile of DG, and a total of 33 chemical constituents were successfully identified. DG significantly alleviated the ischemic damage to brain tissue, reduced infarct volume, and improved neurological dysfunction. The content of Fe2+and lipid peroxidation products was markedly decreased. Furthermore, DG could restore the expression of Nrf2, -xCT, and GPX4 with the inhibition of COX-2, TFR1, and ACSL4, thus achieving a suppressive effect on ferroptosis.Conclusions:The regulatory influence of DG via the Nrf2/System xc-/GPX4 axis may play a crucial role in alleviating ferroptosis and enhancing recovery from cerebral ischemia injury.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Cong Zhang,Yangkun Xiong,Mingyang Gong,Haixia Zhao,Shan Li,Xin Chen,Xiaochuan Ye,Zhenpeng Qiu
Hyperuricemic nephropathy, a common subtype of chronic kidney disease (CKD), has become an important global public health issue and is closely related to the dramatic increase in fructose consumption. Pachymic acid, the primary active ingredient of the edible fungal herb Poria cocos, has demonstrated the protective capacity against renal injury, but its beneficial effect on hyperuricemic nephropathy remains unclear. In this study, a fructose-diet-induced hyperuricemia nephropathy mouse model was established to reveal the efficacy of pachymic acid in inhibiting hyperuricemic nephropathy the progression. Our results showed that pachymic acid restored abnormal renal function indexes and pathological manifestations such as tubular dilatation and glomerular fibrosis in fructose-fed mice. Transcriptome sequencing results showed marked alterations in glutathione metabolism and ferroptosis signaling pathways in the kidneys of fructose-fed mice after pachymic acid treatment. Mechanistically, pachymic acid activated the Nrf2/GPX-4 signaling pathway by directly binding to Nrf2 and promoting its nuclear translocation, thereby inhibiting ferroptosis, oxidative stress, and inflammatory responses in the kidneys of fructose-fed mice. Consistent results were observed in uric acid-treated HK-2 cells. Notably, both Nrf2 inhibitor ML385 and GPX-4 inhibitor RSL3 treatments reversed the protective effects of pachymic acid against renal injury by suppressing ferroptosis in vitro and in vivo. Summary, our study provides compelling evidence that pachymic acid ameliorates renal injury in fructose-fed mice by inhibiting ferroptosis through targeted activating an Nrf2/GPX-4 pathway, suggesting that dietary supplementation with Poria cocos or pachymic acid might be an effective strategy for CKD prevention, particularly in the subtype of fructose-diet-driven hyperuricemic nephropathy.
研究领域:
药理学
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肾脏病学
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生物化学
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分子生物学
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营养学
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药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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