FREE RADICAL BIOLOGY AND MEDICINE
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2025
·
IF 8.2
Keli Liu,Shaofan Hu,Reziyamu Wufuer,Qun Zhang,Lu Qiu,Zhengwen Zhang,Meng Wang,Yiguo Zhang
The levels of reactive oxygen species (ROS) and the extent of ensuing DNA damage significantly influence cancer initiation and progression. Of crucial importance, the aspartate protease DDI2 has been proposed to play a pivotal role in monitoring intracellular ROS levels (to trigger oxidative eustress or distress), as well as in the oxidative DNA damage repair, through redox homeostasis-determining factor Nrf1 (encoded by NFE2L1 ). However, the specific role of DDI2 in the multi-step process resulting in the development and progression of liver cancer remains elusive to date. In the present study, we employed the CRISPR/Cas9 gene editing system to create two nuanced lines of DDI2 knockout (i.e., DDI2 −/− and DDI2 insG/− ) from liver cancer cells. Subsequent experiments indicate that the knockout of DDI2 leads to increased ROS levels in hepatoma cells by downregulating two major antioxidant transcription factors Nrf1 and Nrf2 (encoded by NFE2L2 ), exacerbating endogenous DNA damages caused by ROS and not-yet-identified factors, thereby inhibiting cell proliferation and promoting apoptosis, and ultimately hindering in vivo malignant growth of xenograft tumor cells. Conversely, the restoration of DDI2 expression reverses the accumulation of ROS and associated DNA damage caused by DDI2 knockout, eliminating the subsequent inhibitory effects of DDI2 deficiency on both in vitro and in vivo growth of liver cancer cells. Collectively, these findings demonstrate that DDI2 deficiency impedes liver tumor growth by disrupting its survival environment, suggesting that DDI2 may serve as a novel therapeutic target for anti-cancer strategies aimed at modulating ROS or DNA damage processes.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
Journal of Oceanology and Limnology
·
2024
·Vol. 42
·期 1
·163-173
·
IF 1.3
Ma Dandan,Zhou Qingli,Sui Liying,Guo Qingbin,Liu Huanhuan,Liang Honghe,Li Zhenjing,Sang Zhongna
Deltamethrin (DEL), a commonly used pyrethroid pesticide, results in higher reactive oxygen species (ROS) levels in aquatic animals, which consequently unbalance the redox state. Phlorizin (PHL) is a flavonoid and a natural product promising to prevent or reduce pesticide-induced oxidative stress. Artemia is a micro-crustacean widely used in marine hatcheries and an experimental aquatic organism for environmental toxicology research. This research aimed to evaluate the toxicity of DEL on Artemia and the antioxidative effect of PHL against the toxicity. Results show that 0.08-mg/mL PHL exerted its antioxidative effects on hatching percentage of the cysts in 24-h incubation and on body length and survival rate of Artemia in 12-d culture. After 12-d culture, 12-, 24-, and 36-h DEL exposure showed significant drops in SOD, CAT, and GSH-Px enzyme activities, and significant increases in ROS and malondialdehyde (MDA) levels in Artemia ( P <0.05). On the contrary, 0.08-mg/mL PHL application improved the enzyme activities and decreased the ROS and MDA levels ( P <0.05). Moreover, 0.08-mg/mL PHL significantly increased mRNA expression levels of Cu/Zn SOD, CAT, GST, HO-1, NQO1 , and Nrf2 , and decreased mRNA expression level of Keap1 in the DEL-exposed Artemia ( P <0.05). Therefore, DEL is toxic to Artemia , while PHL alleviates DEL-induced oxidative damage by possibly regulating the Nrf2 signaling pathway. This study provided a theoretical basis for PHL to reduce pesticide-induced toxicity in aquatic animals.
研究领域:
环境毒理学
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水产动物健康
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抗氧化研究
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DOI
高影响因子
Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 6
·1-10
·
IF 2.447
Qian Li,Zhaoyan Qiu,Yan Wang,Chunyan Guo,Xu Cai,Yandong Zhang,Li Liu,Hongkun Xue,Jintian Tang
Tea polyphenols (TPs) are the major bioactive extract from green tea that have been extensively reported to prevent and treat oxidative stress damage. In previous studies, TPs have been demonstrated to protect cells against oxidative injury induced by hydrogen peroxide (H2O2). However, the underlying mechanism remains unclear. The aim of the current study was to investigate whether the protective and regulatory effects of TPs on oxidative stress damage were dependent on the mammalian STE20‑like protein kinase (Mst)/nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) axis and the Kelch‑like ECH‑associated protein 1 (Keap1)/Nrf2/heme oxygenase 1 (HO‑1) pathway in RAW264.7 cells, a murine macrophage cell line. Maintaining a certain range of intracellular reactive oxygen species (ROS) levels is critical to basic cellular activities, while excessive ROS generation can override the antioxidant capacity of the cell and result in oxidative stress damage. The inhibition of ROS generation offers an effective target for preventing oxidative damage. The results of the present study revealed that pretreatment with TPs inhibited the production of intracellular ROS and protected RAW264.7 cells from H2O2‑induced oxidative damage. TPs was also demonstrated to attenuate the production of nitric oxide and malondialdehyde and increase the levels of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase). In addition, following TPs treatment, alterations in Mst1/2 at the mRNA and protein level inhibited the production of ROS and promoted the self‑regulation of antioxidation. TPs‑induced Keap1 gene downregulation also increased the expression of Nrf2 and HO‑1. Collectively, the results of the present study demonstrated that TPs provided protection against H2O2‑induced oxidative injury in RAW264.7 cells.
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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生物化学
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DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Menghao Qiao,Liqun Zhou,Minhua Zhou,Yu Fang,Haiying Mai,Lingbo Cao,Kun Xu,Yuan Sang,Minyi Chen,Jiewei Huang,Peiyi Huang,Zhipeng Yan,Chao Wang,Zhangshuai Dai,Dichun Huang,Ronghan He,Lijuan Pang,Yunmiao Guo,Ting Gang Chew,Junqi Huang
Ferroptosis is an iron-dependent form of programmed cell death governed by redox homeostasis. Although Ezrin, Radixin, and Moesin (ERM) proteins are established membrane-actin cytoskeleton linkers, their role in ferroptosis remains unexplored. Here, ERM proteins are identified as modulators of erastin-induced ferroptosis. In human fibrosarcoma HT-1080 cells, pharmacological inhibition of ERM phosphorylation, knockdown of individual ERM members, or overexpression of a phospho-deficient Ezrin mutant (T567A) consistently attenuated ferroptosis, whereas wild-type ERM overexpression enhances ferroptosis susceptibility. Mechanistically, ERM inhibition leads to F-actin depolymerization accompanied by a modest rise in reactive oxygen species (ROS). F-actin stabilization prevents this ROS surge and restores ferroptotic sensitivity, whereas its depolymerization mimics the protective effect of ERM inhibition. ROS elevation triggers KEAP1 degradation, stabilizing NRF2 and promoting its nuclear translocation. Activated nuclear NRF2 induces antioxidant genes, particularly HMOX1 , a key effector of heme catabolism that enhances redox buffering and limits lipid peroxidation, ultimately conferring resistance to ferroptosis. The protective effects of ERM inhibition are further validated in ferroptosis-relevant ex vivo and in vivo models. Notably, other pro-oxidants similarly attenuate ferroptosis at appropriate concentrations. Together, these results establish ERM proteins as regulators of ferroptosis and reveal an underappreciated group of ferroptosis inhibitors that engage ROS-NRF2-mediated redox-adaptation.
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Xi Wang,Wenjing Zhu,Miao Xing,Haiyan Zhu,Enqing Chen,Jie Zhou
Matrine (MT) is an alkaloid isolated from Sophora flavescens with various bioactivities and is widely used clinically. However, the broader its clinical use, the greater its toxicity concerns. We investigate the role of ferroptosis in MT-induced liver injury caused by an imbalance in the antioxidant pathway. Our results showed that MT could cause pathological changes in liver tissues and lead to a significant reduction in L02 cell viability. MT also reduced superoxide dismutase (SOD) and glutathione (GSH), increased malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation levels, and disrupted iron homeostasis , leading to ferroptosis. In addition, MT decreased the protein levels of FTH, Nrf2 , xCT, GPX4, HO-1 and ferroptosis suppressor protein 1 (FSP1) and increased the protein levels of TRF1 and DMT1 , characteristic indicators of ferroptosis. Interestingly, the cytotoxic effects of MT were alleviated by ferroptosis inhibitor, Nrf2 agonist, or selenium supplementation. These results revealed that MT triggers hepatocyte ferroptosis by inhibiting the Nrf2/GPX4 antioxidant system.
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PubMed
高影响因子
Redox Biology
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2022
·
IF 10.787
Chenxu Ge,Jun Tan,Deshuai Lou,Liancai Zhu,Zixuan Zhong,Xianling Dai,Yan Sun,Qin Kuang,Junjie Zhao,Longyan Wang,Jin Liu,Bochu Wang,Minxuan Xu
Mulberrin (Mul) is a key component of the traditional Chinese medicine Romulus Mori with various biological functions. However, the effects of Mul on liver fibrosis have not been addressed, and thus were investigated in our present study, as well as the underlying mechanisms. Here, we found that Mul administration significantly ameliorated carbon tetrachloride (CCl 4 )-induced liver injury and dysfunction in mice. Furthermore, CCl 4 -triggerd collagen deposition and liver fibrosis were remarkably attenuated in mice with Mul supplementation through suppressing transforming growth factor β1 (TGF-β1)/SMAD2/3 signaling pathway. Additionally, Mul treatments strongly restrained the hepatic inflammation in CCl 4 -challenged mice via blocking nuclear factor-κB (NF-κB) signaling. Importantly, we found that Mul markedly increased liver TRIM31 expression in CCl 4 -treated mice, accompanied with the inactivation of NOD-like receptor protein 3 (NLRP3) inflammasome. CCl 4 -triggered hepatic oxidative stress was also efficiently mitigated by Mul consumption via improving nuclear factor E2-related factor 2 (Nrf2) activation. Our in vitro studies confirmed that Mul reduced the activation of human and mouse primary hepatic stellate cells (HSCs) stimulated by TGF-β1. Consistently, Mul remarkably retarded the inflammatory response and reactive oxygen species (ROS) accumulation both in human and murine hepatocytes. More importantly, by using hepatocyte-specific TRIM31 knockout mice (TRIM31 Hep-cKO ) and mouse primary hepatocytes with Nrf2-knockout (Nrf2 KO ), we identified that the anti-fibrotic and hepatic protective effects of Mul were TRIM31/Nrf2 signaling-dependent, relieving HSCs activation and liver fibrosis. Therefore, Mul-ameliorated hepatocyte injury contributed to the suppression of HSCs activation by improving TRIM31/Nrf2 axis, thus providing a novel therapeutic strategy for hepatic fibrosis treatment.
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PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-16
·
IF 7
Liang Xue,Tian Ruofei,Li Ting,Wang Hao,Qin Yifei,Qian Meirui,Fan Jing,Wang Dan,Cui Hong-Yong,Jiang Jianli
Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe 2+ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.
研究领域:
肿瘤学
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分子生物学
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营养学
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DOI
PubMed
高影响因子
Nutrients
·
2016
·Vol. 8
·期 12
·799
·
IF 3.759
Shu-Fang Xia,Guo-Wei Le,Peng Wang,Yu-Yu Qiu,Yu-Yu Jiang,Xue Tang
Myricetin is an effective antioxidant in the treatment of obesity and obesity-related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high-fat diet (HFD). C57BL/6 mice were fed either a standard diet or a HFD for 12 weeks and then half of the mice were treated with myricetin (0.12% in the diet,w/w) while on their respective diets for further 12 weeks. Myricetin treatment significantly alleviated HFD-induced steatosis, decreased hepatic lipid accumulation and thiobarbituric acid reactive substance (TBARS) levels, and increased antioxidative enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Microarray analysis of hepatic gene expression profiles showed that myricetin significantly altered the expression profiles of 177 genes which were involved in 12 biological pathways, including the peroxisome proliferator activated receptor (PPAR) signaling pathway and peroxisome. Further research indicated that myricetin elevated hepatic nuclear Nrf2 translocation, increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced the protein expression of PPARγ, and normalized the expressions of genes that were involved in peroxisome and the PPAR signaling pathway. Our data indicated that myricetin might represent an effective therapeutic agent to treat HFD-induced hepatic steatosis via activating the Nrf2 pathway and the PPAR signaling pathway.Keywords:myricetin;hepatic steatosis;Nrf2;PPARγ;oxidative stress
研究领域:
药理学
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分子生物学
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营养学
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DOI
PubMed
高影响因子
Frontiers in Sustainable Food Systems
·
2024
·
IF 3.7
Chen Zhaojun,Tan Lulin,Li Lina,Wang Hui,Feng Xin,Liu Xiong,Rao Chaolong
The objective of the present study was to evaluate structure–activity relationships of four sanshools on antioxidant activities. In vitro, hydroxy-α-sanshool (HAS), hydroxy-β-sanshool (HBS), and hydroxy-γ-sanshool (HRS) had stronger antioxidant capacities than hydroxy-γ-sanshool (RS), attributed to the hydroxyl group. Furthermore, HRS had the greatest oxygen radical absorbance capacities (ORAC) and free radical scavenging (DPPH and ABTS) capacities, attributed to more cis-double bonds. Sanshools could effectively decrease the level of oxidative stress in colonic tissue and HCT-116 cells, including increased enzyme activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) and decreased concentrations of malondialdehyde (MDA). After intragastric administration of sanshool, HRS increased the the level of hepatic Total antioxidant capacity (T-AOC) and colon GSH-Px and SOD. Moreover, sanshools significantly increased Nrf2, HO-1 proteins and decreased Keap1 protein. The protective effect of HRS was much higher than HAS, HBS, and RS, apparently due to its amide and hydroxyl groups. The binding energies of Nrf2 with HAS, HBS, HRS, and RS were −5.17, −5.11, −5.75, and −4.16 kcal/mol, respectively. HRS is more easily combine with Nrf2. In summary, sanshools acted as substitutes for natural antioxidants, in which HRS has the greatest antioxidant activity. This study provided a basis for future research on relationships between structure and activity.
研究领域:
植物化学
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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
Current Computer-Aided Drug Design
·
2024
·Vol. 21
·期 4
·503-516
·
IF 1.5
Xiaoyan Meng,Xinming Yan,Peng Xue,Zhaoqing Xi
ObjectiveThis study utilized transcriptomic sequencing combined with cellular and animal models to explore the potential mechanisms of Xuebijing in treating sepsis-induced myocardial dysfunction, also known as sepsis-induced myocardial injury.MethodsWe investigated potential targets and regulatory mechanisms of XBJ injection using network pharmacology and RNA sequencing. The effects of XBJ on oxidative stress and apoptosis levels in human cardiac myocytes (AC16) and C57BL/6 mice exposed to lipopolysaccharide (LPS) were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA), fluorescent probe, Fluorescent Quantitative Polymerase Chain Reaction (qPCR), Western Blot, Transmission Electron Microscopy, oxidative stress-related indicators detection kit, flow cytometry, and Immunohistochemistry (IHC).ResultsFirst, it was verified that XBJ can reduce the deformation of AC16 cardiomyocytes induced by LPS and the production and secretion of ROS (P <0.01). The transcriptome sequencing results showed that the TRIM16 gene was significantly increased after XBJ treatment, and the data of KEGG and GO analyses demonstrated that XBJ could inhibit the pathway expression of oxidative stress damage in AC16 cells, and PCR verified that XBJ could indeed increase the expression level of TRIM16 gene in AC16 cells (P <0.01). Basic animal and cell experiments showed that LPS could inhibit the expression of TRIM16 and NRF2 in cardiomyocytes (P <0.05) and promote the expression of Keap1 (P <0.01), while XBJ could significantly up-regulate the expression levels of TRIM16 and NRF2 (P <0.01) and inhibit the expression of Keap1 (P <0.01), thereby affecting the expression levels of downstream proinflammatory cytokines and alleviating LPS-induced oxidative stress damage. In addition, XBJ also inhibited the expression of the pro-apoptotic proteins Bax and c-caspase3 (P <0.01), promoted the expression of the anti-apoptotic protein Bcl2 (P <0.01), and reduced LPS-induced apoptosis by upregulating TRIM16.ConclusionOur comprehensive data demonstrated that TRIM16 is a key gene in the therapeutic action of Xuebijing in sepsis-induced myocardial dysfunction, protecting myocardial cells from injury through antioxidative stress and anti-apoptotic mechanisms.
研究领域:
医学
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分子生物学
·
药理学
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DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
·
IF 2.705
Jianfa Wu,Li Zhang,Huixin Li,Suqin Wu,Zhou Liu
Cisplatin resistance is a vital obstacle for the prognosis of ovarian cancer. However, the mechanism of cisplatin resistance is still unknown. This research was performed to explore the role of Nrf2 (nuclear factor, erythroid 2 like 2) and CD99 (CD99 molecule) in cisplatin resistance in ovarian cancer. QRT-PCR and Western blot were used to detect the expression of CD99 in ovarian cancer cells and tissues with different cisplatin sensitivities. Cell viability was analyzed by the Cell Counting Kit-8 (CCK8). The relationship of Nrf2 and CD99 was assessed by dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP). Bioinformatics analysis was performed to search for the downstream gene of CD99. In this study, it was revealed that CD99 was highly expressed in cisplatin-resistant ovarian cancer cells and tissues, while lower CD99 expression was found in cisplatin-sensitive ovarian cancer cells and tissues. In addition, the overexpression of CD99 resulted in cisplatin resistance; on the other hand, knockdown of CD99 sensitized ovarian cancer to cisplatin. Furthermore, survival analysis indicated that overall survival (OS) and progression-free survival (PFS) of patients with higher CD99 expression were shorter than those with lower CD99 expression. It was also found that when Nrf2 was upregulated in cisplatin-sensitive ovarian cells, CD99 expression and cell viability increased after cisplatin treatment. Knockdown of CD99 could reverse cisplatin resistance induced by Nrf2. Conversely, when Nrf2 was knocked down in cisplatin-resistant ovarian cancer cells, CD99 expression and cell viability with cisplatin treatment decreased, while simultaneously upregulating CD99 reactivated cisplatin resistance in ovarian cancer cells. The dual-luciferase reporter gene assay and ChIP analysis suggested CD99 was a downstream gene of Nrf2, and Nrf2 positively regulated the expression of CD99 at the transcriptional level. In conclusion, Nrf2 induced cisplatin resistance in ovarian cancer cells by promoting CD99 expression. Targeted CD99 might be an effective way to reverse cisplatin resistance in ovarian cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2026
·
IF 3.5
Yurou Li,Zhenzhen Yan,Wanrong Zhang,Xin Zheng,Zhengping Wu,Yinjie Jiang,Jie Zhou
Sodium aescinate (SA), a triterpenoid saponin derived from Aesculus hippocastanum seeds, is widely used clinically but has been linked to hepatotoxicity, nephrotoxicity, and phlebitis. We previously reported that SA triggers hepatocyte ferroptosis, and enhancing GSH synthesis via the CTH/cysteine axis activation only partially mitigates liver injury. In this study, we showed that SA disrupted redox homeostasis, promoted lipid peroxidation (LPO), and induced ferroptosis in hepatocytes, concomitant with suppressed Nrf2/PRDX6/GPX4 pathway activity. Mechanistically, SA downregulated the expression and transcriptional activity of Nrf2, reducing its binding to antioxidant response elements (AREs) in the promoters of PRDX6 and GPX4, thereby decreasing their expression. Nrf2 overexpression restored PRDX6 and GPX4 levels, enhanced antioxidant capacity, and attenuated SA-induced ferroptosis. Notably, PRDX6 regulated GPX4 expression and activity by modulating selenium utilization and selenoprotein biosynthesis during SA-induced hepatotoxicity. Both PRDX6 overexpression and selenium supplementation rescued GPX4 and protected against SA-induced ferroptotic damage. The protection conferred by Nrf2/PRDX6 overexpression or selenium supplementation was fully abrogated upon GPX4 knockdown or inhibition with RSL3. Collectively, SA induced ferroptotic liver injury by disrupting the Nrf2/PRDX6/GPX4 axis, culminating in GPX4 deficiency and redox collapse. This study suggests that this cascade represents a promising therapeutic target for SA-induced hepatotoxicity.
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PubMed
高影响因子
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