JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Yufei Cao,Yiqiang Zhang,Boran Zhou,Yingxue Zhang,Xu Han,Xinyuan Luan,Yu Wang,Hongjing Zhao
Zearalenone (ZEN) is a mycotoxin that induces hepatic oxidative injury by promoting ROS accumulation and compromising antioxidant defenses. Transcriptomic profiling revealed xanthine oxidase (XOD) as a key mediator. Structure-based molecular docking identified polydatin (PD) from Polygonum cuspidatum as a potent XOD inhibitor with strong binding affinity. Biochemical assays confirmed PD’s XOD inhibition. In vitro and in vivo studies demonstrated that PD significantly attenuated ZEN-induced oxidative stress, reduced ROS generation, and improved pathological markers of liver injury, with optimal efficacy at low concentrations. Molecular dynamics simulations revealed PD forms a stable complex with XOD. Concurrently, PD activated the Nrf2/HO-1 pathway, enhancing SOD and GSH-Px expression while reducing lipid peroxidation. These findings demonstrate that PD mitigates ZEN hepatotoxicity through dual mechanisms: direct XOD inhibition and enhancement of endogenous antioxidant capacity, supporting its therapeutic potential.
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ANTIOXIDANTS & REDOX SIGNALING
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2025
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IF 6.1
Xian-Dong Li,Yue-Xin Ning,Yi-Feng Pei,Jing-Yuan Niu,Jian Luo,Yi-Na Zhang,Zi-Ai Zhao,Xiao-Wen Hou,Qian-Kun Zhao,Tian-Ce Xu,Hui-Sheng Chen
Aims: Cathodal transcranial direct current stimulation (C-tDCS), a noninvasive physical therapy, has potential neuroprotective effects in acute ischemic stroke. However, the rational timing of its application and the underlying mechanisms remain inadequately understood. This study aims to investigate its neuroprotective effects and the involved mechanisms.Results: Our in vivo results indicated that C-tDCS applied during the reperfusion phase but not during the ischemic phase significantly improved neurological outcomes, reduced infarct volume, and mitigated histopathological damage in middle cerebral artery occlusion/reperfusion rats. C-tDCS during the reperfusion phase suppressed ferroptosis, activated nuclear factor erythroid 2-related factor 2 (Nrf2), and inhibited mitophagy. In vitro, the ferroptosis inducer RSL3 negated the protective effects of cathodal direct current stimulation on HT22 neuronal cells subjected to oxygen-glucose deprivation/reoxygenation injury. Furthermore, the Nrf2 inhibitor ML385 and the mitophagy activator FCCP reversed the inhibitory effects of C-tDCS on ferroptosis, with FCCP also affecting Nrf2 activation by C-tDCS.Innovation and Conclusions: These results demonstrate that C-tDCS during reperfusion attenuates cerebral ischemia-reperfusion injury by coordinating mitophagy inhibition and Nrf2 activation to counteract ferroptosis, which provides new evidence for its potential translational clinical applications. Antioxid. Redox Signal. 00, 000–000.
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Frontiers in Bioscience-Landmark
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2025
·Vol. 30
·期 6
·36615
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IF 3.1
Shanli Wu,Gun Yang,Xiaosha Wen,Yi Lin,Shenglong Wang,Jing Wang,Quan Liu,Dixian Luo
Background:Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC).Methods:Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels.Results:Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1.Conclusions:AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.
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FITOTERAPIA
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2025
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IF 2.6
Liyuan Shen,Jingwen Xu,Yihai Wang,Jiaming Yao,Xiangjiu He
Chronic myeloid leukemia (CML) is a myeloproliferative tumor, which is prone to drug resistance during treatment. Previous studies have indicated that Ficus altissima Blume exhibits potential antitumor properties, with 5,7,2′-trihydroxy-4′-methoxy-6-(3-hydroxy-3-methylbutyl)-isoflavone (TMI) as its main active component. However, the antitumour activity of TMI and its underlying mechanisms remain unexplored. This study investigated the anti-proliferative effects of TMI on adriamycin (ADR)-resistant leukemia K562 cells (K562/ADR cells) and the mechanism of overcoming multidrug resistance (MDR). The findings demonstrated that TMI significantly downregulated P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) expression. It was confirmed that TMI triggered caspase-dependent apoptosis in K562/ADR and K562 cells. While reactive oxygen species accumulation and PI3K/AKT/mTOR mediated TMI's effect in K562 cells, these pathways were irrelevant to its apoptosis induction and MDR overcoming in K562/ADR cells. Further research found that the nuclear factor erythroid 2-related factor 2 (Nrf2) expression was significantly suppressed by TMI treatment. In contrast, exposure to the Nrf2 agonist tert-butylhydroquinone resulted in upregulation of P-gp and BCRP protein levels in K562/ADR cells. This suggests that TMI's overcoming of K562/ADR cell drug resistance is associated with Nrf2 degradation. Finally, molecular docking analysis and cellular thermal shift assay experiments showed that TMI exerted anti-drug resistance effect by directly binding to Nrf2 protein. Collectively, TMI overcomes K562/ADR cell resistance primarily through targeting and inhibiting Nrf2 protein and decreasing drug efflux protein expression, ultimately promoting cell death. These results highlight TMI's potential as a drug-resistant leukemia therapy, while also suggesting that developing Nrf2-targeted inhibitors may represent a novel strategy for overcoming tumor drug resistance.
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JOURNAL OF MOLECULAR HISTOLOGY
·
2025
·Vol. 56
·期 6
·1-14
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IF 2.2
Liang Jia-Jun,Liu Hong-Xia,Yan Jian-Gang,Xie Guo,Liu Wen-Li,Lin Jia-Hui,Li Xiao-Min,Mao Xin-Liang
The specific hepatoprotective mechanism of Fermented Panax ginseng C.A. Meyer extract (FGE) has not yet been fully elucidated. In this study, an AAPH-induced liver injury model was established to investigate the hepatoprotective effects of FGE. The hepatoprotective effects of FGE may involve the mediation of the NRF2 pathway by rare ginsenosides such as 20(R)-Rh1, 20(S)-Rg2, Rg5, 20(R)-Rg2, and 20(S)-Rh1. The results showed that FGE effectively improved pathological damage and liver dysfunction, increased SOD and GPx expression in the liver, and inhibited excessive ROS generation both in vivo and in vitro. Mechanistically, FGE regulated the mRNA and protein expression of KEAP1, HO-1, and NQO1, while enhancing NRF2 protein expression and promoting its nuclear translocation. In conclusion, the NRF2 signaling pathway activated by FGE may inhibit AAPH-induced oxidative stress and alleviate the resulting liver injury. Graphical abstract
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NEUROCHEMICAL RESEARCH
·
2018
·Vol. 43
·期 12
·2435-2445
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IF 2.772
Zhang Man,Huang Li-Li,Teng Chen-Huai,Wu Fang-Fang,Ge Li-yun,Shi Yu-Juan,He Zheng-Le,Liu Lei,Jiang Cheng-Jie,Hou Ruo-Nan,Xiao Jian,Zhang Hong-Yu,Chen Da-Qing
Traumatic brain injury (TBI) is a serious public health and medical problem worldwide. Oxidative stress plays a vital role in the pathogenesis of TBI. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important factor in the cellular defense against oxidative stress, is activated following TBI. In this study, the protective effects of Isoliquiritigenin (ILG), a promising antioxidant stress drug, was evaluated as a protective agent against TBI. In a mouse model of controlled cortical impact Injury, we found that the ILG administration reduced the Garcia neuroscore, injury histopathology, brain water content, cerebral vascular permeability, the expression of cleaved caspase3, aquaporin-4, glial fibrillary acidic protein and the increased the expression of neurofilament light chain protein, indicating the protective effects against TBI in vivo. ILG treatment after TBI also restored the oxidative stress and promoted the Nrf2 protein transfer from the cytoplasm to the nucleus. We then used Nrf2−/− mice to test the protective effect of Nrf2 during ILG treatment of TBI. Our findings indicated that Nrf2−/− mice had greater brain injury and oxidative stress than wild-type (WT) mice and ILG was less effective at inhibiting oxidative stress and repairing the brain injury than in the WT mice. In vitro studies in SY5Y cells under oxygen glucose deprivation/re-oxygenation stimulation yielded results that were consistent with those obtained in vivo showing that ILG promotes Nrf2 protein transfer from the cytoplasm to the nucleus. Taken together, our findings demonstrate that Nrf2 is an important protective factor against TBI-induced injuries, which indicates that the protective effects of ILG are mediated by inhibiting oxidative stress after TBI via a mechanism that involves the promotion of Nrf2 protein transfer from the cytoplasm to the nucleus.
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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细胞生物学
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LIFE SCIENCES
·
2018
·
IF 3.234
Runxiao Lv,Lili Du,Lixin Zhang,Zhiqiang Zhang
Aims Spinal cord injury (SCI) is one of the most devastating central lesions, resulting in serious locomotor deficit. Polydatin is a glucoside of resveratrol with proven anti-cardiovascular, anti-inflammatory and anti-oxidative properties. The main purpose of this study was to investigate whether polydatin could alleviate SCI in rats and explore the underlying mechanisms. Materials and methods SCI rats induced by a weight-drop device were treated with intraperitoneal injection of 20 or 40 mg/kg polydatin. Then the locomotor function of SCI rats was evaluated by the Basso, Beattie and Bresnahan locomotor rating scale, spinal cord edema was measured by the wet/dry weight method, oxidative stress markers were detected by commercial kits and cell apoptosis status was measured by TUNEL staining. In addition, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) production and apoptosis status were detected in murine microglia BV2 cells treated with 100 ng/ml lipopolysaccharides (LPS) and 4.0 μM polydatin. The expression of apoptosis-related proteins involved in nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was measured by western blot. Key findings Our data showed that polydatin treatment improved locomotor performance of SCI rats, as well as reduced oxidative stress and inhibited apoptosis by enhancing Nrf2/HO-1 signaling. In addition, polydatin was found to up-regulate Nrf2 activity and the inhibitory effects of polydatin on oxidative stress and apoptosis in LPS-stimulated BV2 microglia was neutralized by silencing Nrf2 using specific siRNA. Significance We demonstrate that polydatin may protect the spinal cord from SCI by suppression of oxidative stress and apoptosis via improving Nrf2/HO-1 signaling in microglia.
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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CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Yana Ma,Wen Luo,Weijia Zhu,Zhichao Deng,Shijun Xu,Hang Yuan,Wei-jun Fan,Quanjun Yao,Wei Yao,Ho-Young Song,Mingzhen Zhang,Jizhao Wang,Hongtao Hu
Oxidative stress, resulting from excessive reactive oxygen species (ROS), is critically involved in the development and progression of inflammatory diseases such as inflammatory bowel disease. Therefore, targeting ROS for the treatment of inflammation holds great potential, and the underlying mechanism is of great significance for clinical medication. In this work, carbon dots (C-dots) based on chrysanthemum as carbon source were obtained through a hydrothermal method. The as-prepared C-dots exhibited favorable ROS scavenging capacity and biocompatibility. The ROS level and the oxidative damage were reversed, the expression of proinflammatory factors was reduced, and the disrupted barrier was recovered by chrysanthemum-derived C-dots in the cellular inflammatory model. The anti-inflammatory effects were also validated in mice colitis model. Mechanistically, the chrysanthemum-derived C-dots regulated the Keap1/Nrf2 antioxidant signaling and inhibited the NF-κB/NLRP3 inflammasome-mediated inflammatory signaling, thereby restoring redox homeostasis and modulating the inflammatory microenvironment. Collectively, the C-dots from chrysanthemum with preferable biocompatibility hold a bright prospect in inflammation resolution through remodeling redox and inflammatory microenvironment.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2022
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IF 7.088
Yaoqiang Lao,Yang Wang,Jianwen Chen,Ping Huang,Ruiqi Su,Jinguo Shi,Caibao Jiang,Jingxia Zhang
Acute ischemic stroke is a leading cause of disability and death. The development of neuroprotectants is an emerging strategy for the treatment of ischemic stroke. In this work, we designed and synthesized a series of 1,3,5-triaryl substituent triazole derivatives by introducing a phenolic group and phenyl ring to 3,5-diaryl substituents oxadiazole . Structure-activity relationship (SAR) analysis showed that compounds with alkyl groups or with substituents at the 3-position possessed better protective effects. Among the derivatives, 3,5-dimethyl substituted compound 24 exhibited the best neuroprotective effect with weak cytotoxicity. Compound 24 possessed a high plasma protein binding rate, moderate hERG inhibition, low acute toxicity , and suitable pharmacokinetic properties. In vivo experiments demonstrated that compound 24 exerted a protective effect by reducing cerebral infarction size , improving neurological behavior, and restoring redox balance in middle cerebral artery occlusion rats. Further investigation indicated that compound 24 exerted a protective effect against sodium nitroprusside (SNP) induced cell damage by scavenging intracellular reactive oxygen species and restoring mitochondrial membrane potential . Moreover, compound 24 induced the nuclear translocation of Nuclear factor erythroid 2-related factor (Nrf2) and promoted the generation of antioxidative proteins, including Heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase (NQO1), and glutamate-cysteine ligase catalytic (GCLC). Surface plasmon resonance (SPR) experiments indicated that compound 24 might activate the Nrf2 signaling pathway by interacting with the Keap1 Kelch domain . Taken together, these facts indicate that compound 24 might have potential in the treatment of ischemic stroke.
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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2023
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IF 3.9
Mengyuan Zhou,Jingchao Qiang,Jiajie Gan,Xuhui Xu,Xing Li,Shuai Zhang,Baoshi Xu,Zibo Dong
One of the most often used insecticides is Avermectin (AVM), which is toxic to aquatic organisms. Quercetin (Que) is a fruit and vegetable rich flavonoid with antioxidant activity. Fish gills are the most important respiratory organ. Carp is a biological model for studying environmental toxicology. To better understand the mechanism by which Que reduces AVM-induced gill damage in carp, we created a carp model with AVM and Que supplementation. In this study, four groups were created: the Control group, the Que group (400 mg/kg), the AVM group (2.404 μg/L), and the Que plus AVM group. The analytical methods used in this study were pathological structure examination, QPCR, Reactive Oxygen Species (ROS) and Western blot. The results showed that Que alleviated AVM-induced oxidative stress, inflammatory damage and apoptosis in the gill tissues of carp by activating the Nrf2 pathway. The mechanism was that Que alleviated the accumulation of ROS, reduced the balance between oxidation and antioxidant disrupted by AVM exposure, lowered the content of lipid peroxidation product malondialdehyde (MDA), and increased the content of antioxidant enzymes glutathione (GSH) and catalase (CAT). The Nrf2 pathway was activated. Meanwhile, Que inhibited apoptosis in the gills of carp by decreasing the levels of Bax, Cytochrome C(Cytoc), Caspase9, Cleaved-Caspase3, and elevating Bax. This is significant for future studies on Que and AVM. New recommendations are provided to reduce the threat of pollution in the water environment.
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BMC Complementary Medicine and Therapies
·
2023
·Vol. 23
·期 1
·1-16
·
IF 3.9
Ma Jianping,Zheng Miao,Zhang Xinyue,Lu Jiaqi,Gu Lili
Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative and remains incurable. Aluminum is a potent neurotoxin associated with AD. The main pathological features of AD are extracellular amyloid-β protein deposition and intracellular hyperphosphorylated Tau protein. A body of evidence suggest that oxidative stress and autophagy are involved in the pathogenesis of AD. Andrographis paniculata (AP) is a native plant with anti-inflammatory, anti-oxidative stress, and regulation of autophagy properties. AP significantly alleviated cognitive impairments, reduced Aβ deposition and has neuroprotective effect. However, its effects on aluminum-induced AD model have not been studied much. In this study, we investigated whether AP protect against aluminum-induced neurotoxicity through regulation of p62-Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathway and activation autophagy in vivo and in vitro.Methods UPLC-ESI-qTOF-MS/MS was used to identify the chemical constituents of AP ethanol extract. The mice with cognitive deficit were established by injecting aluminum chloride and D-galactose, and treated with either AP extract (200, 400, or 600 mg/kg/d) or andrographolide (2 mg/kg/2d).The spatial memory ability was detected by Morris water maze, HE staining were used to detect in brain tissue,Oxidative stress indexs and SOD activity in both serum and brain tissue were detected by kit.The expression of p62-Nrf2 pathway proteins were measured via western blotting. Furthermore, the neurotoxicity model was induced by aluminum maltolate (700 µM) in PC12 cells. Following AP and andrographolide treatment, the cell viability was detected. The relevant mRNA and protein expressions were detected in cells transfected with the p62 siRNA.Results The main active components of AP included andrographolide, neoandrographolide and deoxyandrographolide as identified. AP and andrographolide significantly improved the spatial memory ability of mice, attenuated pathological changes of hippocampal cells, reduced the level of malondialdehyde, and increased superoxide dismutase activity in serum or brain tissue as compared to model control. In addition, the Nrf2, p62 and LC3B-II proteins expression were increased, and p-Tau and Keap1 proteins were decreased in the hippocampus after AP and andrographolide treatment.Furthermore, AP increased aluminum maltolate-induced cell viability in PC12 cells. Silencing p62 could reverse the upregulation expression of Nrf2 and downregulation of Keap1 and Tau proteins induced by AP in aluminum maltolate-treated cells.Conclusion sAP had neuroprotective effects against aluminum -induced cognitive dysfunction or cytotoxicity, which was involved in the activation of the p62-keap1-Nrf2 pathway and may develop as therapeutic drugs for the treatment of AD. However, this study has certain limitations, further optimize the protocol or model and study the molecular mechanism of AP improving AD.
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ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Ming Liu,Xu Zhou,Xiao-Jie Wang,Yong-Sheng Wang,Sheng-Ji Yang,Zhi-Ming Ding,Shou-Xin Zhang,Li-Dan Zhang,Ze-Qun Duan,Ai-Xin Liang,Li-Jun Huo
Bisphenol AF (BPAF), a BPA-substitute, has been widely used in industrial compounds throughout the world. Several studies have shown that BPAF has endocrine interference and reproductive toxicity. However, the toxic effects of BPAF on pregnancy and placenta of goats are still unclear. Therefore, the objective of this study was to reveal the toxic effect of BPAF by using an in vitro culture model of caprine endometrial epithelial cells (EECs) and further attempted to alleviate the toxicity by curcumin pretreatment. The results showed that BPAF induces significant effects on EECs, including decreased cell viability and mitochondrial membrane potential (△ψm), elevating intracellular reactive oxygen species (ROS), promoting cell apoptosis through upregulating the expression of Bax, Cytochrome c, and downregulating the expression of Bcl-2. Meanwhile, BPAF induced dysregulation of oxidative stress by increasing the levels of malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) but decreasing the activities of superoxide dismutase (SOD). However, curcumin pretreatment could significantly attenuate BPAF-induced toxic effects in EECs. Further study revealed that BPAF treatment could activate mitogen-activated protein kinase (MAPK) pathway and nuclear factor-erythroid 2-related factor 2 (Nrf2) expression, but curcumin pretreatment significantly inhibited the activation of MAPK signal pathway and Nrf2 expression induced by BPAF. Overall, this study indicated that curcumin could prevent BPAF-induced EECs cytotoxicity, which provides a potential therapeutic strategy for female infertility associated with BPAF exposure.
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