BIOFACTORS
·
2019
·Vol. 45
·期 4
·563-574
·
IF 3.598
Fuqiang Liang,Weiwei Cao,Yuting Huang,Yajing Fang,Yuxin Cheng,Siyi Pan,Xiaoyun Xu
Isoflavones are one group of the major flavonoids and possess multiple biological activities due to their antioxidant properties. However, a clear antioxidant mechanism of dietary isoflavones is still remained to be answered. In this study, the effects of isoflavones on the nuclear factor E2-related factor 2 (Nrf2)–antioxidant response element (ARE) signaling pathway and the underlying molecular mechanisms were investigated. Results showed that isoflavones are potential Nrf2–ARE activators while their activities were structure dependent. Biochanin A (BCA), an O -methylated isoflavone with low direct antioxidant activity, can effectively protect HepG2 cells against tert -butyl hydroperoxide ( t -BHP)-induced oxidative damage via activation of the Nrf2 signaling, and thereby the induction of downstream cytoprotective enzymes including NAD(P)H quinone oxidoreductase-1, heme oxygenasae-1, and glutamate-cysteine ligase catalytic subunit. A molecular docking study revealed that BCA could directly bind into the pocket of Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a cytoplasmic suppressor of Nrf2, to facilitate Nrf2 activation. The upstream mitogen-activated protein kinase (MAPK) pathways were also involved in the activation of Nrf2 signaling. These findings indicate that the protective actions of dietary isoflavones against oxidative damage may be at least partly due to their ability to enhance the intracellular antioxidant response system by modulating the Nrf2−ARE signaling pathway.
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Antioxidants
·
2026
·Vol. 15
·期 9
·1207
·
IF 8.2
Kaiwen You,Yixuan Li,Wanqing Zhong,Jie Yu,Yamei Wu,Yuqi Guo,Haoyang Liu,Haiping Xie,Kai Yuan,Yihong Chen,Lei Wang
Due to the hypoxic environment caused by global warming and intensive aquaculture process, fish are susceptible to oxidative damage and death.Eucommia ulmoidesextract (EUE) has demonstrated antioxidant and anti-inflammatory properties. However, whether EUE can mitigate hypoxia-induced negative effects remains uninvestigated in fish. This study investigated the effect of 0 and 1.0 g/kg EUE on acute hypoxia-induced damage in largemouth bass and its potential mechanisms. The results showed that EUE alleviated the deterioration of plasma activities (ALT and AST) induced by acute hypoxic stress, decreased the number of macrophages and increased the total number of blood cells. EUE was effective in reducing the level of apoptosis and the content of ROS, Ca2+, and NO in blood cells. Additionally, EUE alleviated liver tissue injury caused by acute hypoxic stress, which could be associated with increased total antioxidant capacity and antioxidant enzyme activities (SOD, CAT and GSH-Px). Furthermore, EUE up-regulated the expression levels ofNrf2andCAT, activatedXBP1andIREexpression and down-regulatedGRP78expression, relieving the endoplasmic reticulum (ER) stress response. The down-regulation ofCaspase3andCaspase9is evidence that EUE inhibited apoptosis in acute hypoxic stress. In summary, EUE reduced oxidative damage, ER stress, and apoptosis caused by hypoxic stress via the Nrf2/Keap1 signaling pathway in largemouth bass. This study presents a part of the theoretical foundation for the EUE to resist damage caused by hypoxic stress, thereby establishing a basis for sustainable development in aquaculture.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
WenBin Liu,ZhengWei Tan,YueChao Zhao,YanNa Zhao,XiaoLing Yu,BoLin Wang,FengLin Shen,Ai Mi,JinJian Lan,RuiLan Gao
Panaxadiol saponin (PND) is a latent targeted drug for the treatment of aplastic anemia (AA). In this study, we examined the effects of PND on ferroptosis in iron-overload AA and Meg-01 cells. We utilized RNA-seq to analyze differentially expressed genes in iron-induced Meg-01 cells treated with PND. The effects of PND or combined with deferasirox (DFS) on iron deposition, labile iron pool (LIP), several ferroptosis events, apoptosis, mitochondrial structure, as well as ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR pathway-related markers in iron-induced Meg-01 cells were examined by Prussian-blue staining, flow cytometer, ELISA, Hoechst 33342 staining, transmission electron microscope, and Western blot assays, respectively. Additionally, an AA mice model with iron overload was established. Then, the blood routine was assessed, and the number of bone marrow-derived mononuclear cells (BMMNCs) in mice was counted. Also, serum iron, ferroptosis events, apoptosis, histology, T lymphocyte percentage, ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related targets in primary megakaryocytes of AA mice with iron overload were assessed by commercial kits, TUNEL staining, hematoxylin and eosin (H&E) staining, Prussian blue staining, flow cytometer, and qRT-PCR analysis, respectively. PND suppressed iron-triggered iron overload, and apoptosis, and ameliorated mitochondrial morphology in Meg-01 cells. Importantly, PND ameliorated ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related marker expressions in iron-induced Meg-01 cells or primary megakaryocytes of AA mice with iron overload. Moreover, PND ameliorated body weight, peripheral blood cell counts, the number of BMMNCs, and histological injury in the iron-overload AA mice. Also, PND improved the percentage of T lymphocytes in the iron-overload AA mice. PND attenuates ferroptosis against iron-overload AA mice and Meg-01 cells via activating Nrf2/HO-1 and PI3K/AKT/mTOR pathway and is a promising novel therapeutic candidate for AA.
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ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2022
·
IF 5.785
Tian-Ning Yang,Xue-Nan Li,Xiao-Wei Li,Jin-Yang Li,Yue-Qiang Huang,Jin-Long Li
As a plasticizer , di-2-ethylhexyl phthalate (DEHP) has been listed as a potential endocrine disruptor by The World Health Organization. The toxicity of DEHP has been widely studied, but its toxicity on the digestive tract of birds has not been clarified. Female quail were treated by gavage with DEHP (250, 500, 750 mg/kg), with the blank and vehicle control groups reserved. The result showed that DEHP raised the damage severity grade, and decreased the ratio of villus length to crypt depth. The content and activity of cytochrome P450 system (CYP450s) were increased by DEHP. DEHP interfered with the transcription of nuclear xenobiotic receptors (NXRs), CYP isoforms, and the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway. This study revealed DEHP could cause the imbalance in CYP450s mediated by NXRs, and then promote Nrf2 mediated antioxidant defense. This study provided new evidence about the mechanisms of DEHP-induced toxic effects on digestive tract.
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JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2024
·
IF 3.3
Weiyin Xu,Peng Yu,Simeng Shao,Zhaoyang Xie,Yi Wu,Jianing Liu,Tianyang Xu,Guangzhi Cai,Hongmei Yang
Background Our objective in this study is to evaluate the effectiveness of the oligosaccharides extracted from black ginseng (BG), innovatively prepared by a low-temperature steam-heating process, in the improvement of learning and memory impairment in mice, as well as the mechanism(s). Results 8 carbohydrates involving isomaltose and maltotetraose were detected in BG, where the monosaccharide residues including mannose and rhamnose were discovered too. OSBG-treated mice showed significant amelioration in recognition and spatial memory deficits compared to the scopolamine (SCO) group. OSBG could decrease acetylcholinesterase (AChE) activity in a tissue-dependent fashion but not in a dose-dependent manner. Furthermore, in contrast, OSBG administration resulted in significant upregulation superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and Kelch-like ECH-associated protein 1 (Keap1), downregulation of malondialdehyde (MDA) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the tissues. Finally, at the genus level, we observed that the OSBG interventions increased the relative abundance of probiotics ( e.g. , Barnesiella, Staphylococcus , Clostridium_XlVb ,) and decreased pernicious bacteria such as Eisenbergiella and Intestinimonas , compared to the AD mouse model group. Herein, our results demonstrate that OSBG restores the composition of the scopolamine-induced intestinal microbiota in mice, providing a homeostasis of gut microbiota and providing evidence for microbiota-regulated therapeutic potentials of it. Conclusion Our results showed for the first time a clear role for OSBG in improving scopolamine-induced memory impairment by inhibiting cholinergic dysfunction in a tissue-dependent manner. Additionally, OSBG administration relieved oxidative stress by activating the Keap-1/Nrf2 pathway and modulating the gut microbiota. Collectively, OSBG may be a promising target for neuroprotective antioxidants for improving memory and cognition in AD patients. This article is protected by copyright. All rights reserved.
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POULTRY SCIENCE
·
2025
·
IF 4.2
Yulong Li,Shu Wang,Rui Feng
Cadmium (Cd) is a non-essential heavy metal that is highly toxic to testicle. Selenium (Se) is known to possess antagonistic effects against Cd toxicity, yet the precise mechanisms through which Se counteracts Cd-induced testicular damage in chickens through Nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling pathway, oxidative stress (OS), apoptosis, and inflammation remained unclear. In the present study, the experimental model of chicken testis was established by incorporating CdCl 2 and Na 2 SeO 3 into the dietary intake. After 60 days, chickens from each group were euthanized, and testicular and serum samples were subsequently collected. Ultrastructural assessment revealed that Se supplementation significantly mitigated the testicular damage induced by Cd. Se effectively suppressed the Cd-induced elevation in ROS, MDA, and H 2 O 2 levels, while also preventing the downregulation of CAT, GSH, and T-AOC levels. Furthermore, Se administration ameliorated the reduction in the expression levels of Nrf2, HO-1, and Bcl-2 induced by Cd, and counteracted the overexpression of Caspase-3, Bax, Cyt-c, and Caspase-9, TNF-α, IL-2, IL-6, and IL-1β. Meanwhile, immunofluorescence data demonstrated that Se attenuated the Cd-induced decrease in Nrf2 and HO-1 expression and the upregulation of IL-6 expression. In conclusion, this study elucidated that Se might mitigate Cd-induced oxidative stress in chicken testicles through the stimulation of the Nrf2/HO-1 signaling pathway, thereby inhibiting apoptosis and inflammation, and was beneficial in reducing Cd-induced testicular injury.
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Food Bioscience
·
2024
·
IF 4.8
Mengmeng Zhang,Jingbo Liu,Yiding Yu,Wenshuo Ren,Rui Yuan,Xuanting Liu,Xiaomin Shang,Zhiyang Du,Meng-Lei Xu,Ting Zhang
Genistein (GEN) is the most abundant aglycone in soy isoflavones and is a key factor distinguishing soybeans from other food sources. It holds significant nutritional value and exhibits notable biological activity. However, the low water solubility of genistein limits its widespread application. To improve its water solubility, this study prepared γ-cyclodextrin (γ-CD)/GEN inclusion complexes and investigated their mechanism of action in alleviating hydrogen peroxide-induced oxidative stress damage in PC12 cells. The results showed that γ-CD/GEN could be uniformly and stably dispersed in the system. Cell experiments indicated that γ-CD/GEN significantly increased cell survival after treatment with organic hydrogen peroxide, and promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of glutathione peroxidase 4 (GPx4). It also improved mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels, thereby alleviating cell damage caused by oxidative stress. Further Nrf2 knockdown experiments revealed that γ-CD/GEN failed to provide protection, and no protective effect was observed under RSL3 intervention. In conclusion, γ-CD/GEN exerts antioxidant effects by activating the Nrf2/GPx4 pathway, thereby reducing oxidative stress damage induced by organic hydrogen peroxide, providing a theoretical basis for the development of novel antioxidants.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Menglong Gao,Lishun Dong,Yulong Yang,Jinjin Yan,Yuning Liang,Xiaolin Ma,Min Zhou,Hongfei Wu,Yarong Liu,Min Dai
Atherosclerosis (AS) is the underlying cause of many severe vascular diseases and is primarily characterized by abnormal lipid metabolism. Paeonol (Pae), a bioactive compound derived from Paeonia Suffruticosa Andr., is recognized for its significant role in reducing lipid accumulation. Our research objective is to explore the link between lipid buildup in foam cells originating from macrophages and the process of ferroptosis, and explore the effect and mechanism of Pae on inhibiting AS by regulating ferroptosis. In our animal model, ApoE-deficient mice, which were provided with a high-fat regimen to provoke atherosclerosis, were administered Pae. The treatment was benchmarked against simvastatin and ferrostatin-1. The results showed that Pae significantly reduced aortic ferroptosis and lipid accumulation in the mice. In vitro experiments further demonstrated that Pae could decrease lipid accumulation in foam cells induced by oxidized low-density lipoprotein (LDL) and challenged with the ferroptosis inducer erastin. Crucially, the protective effect of Pae against lipid accumulation was dependent on the SIRT1/NRF2/GPX4 pathway, as SIRT1 knockdown abolished this effect. Our findings suggest that Pae may offer a novel therapeutic approach for AS by inhibiting lipid accumulation through the suppression of ferroptosis, mediated by the SIRT1/NRF2/GPX4 pathway. Such knowledge has the potential to inform the creation of novel therapeutic strategies aimed at regulating ferroptosis within the context of atherosclerosis.
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CELLULAR SIGNALLING
·
2025
·
IF 3.7
Mengxin Li,Wanqi Wu,Zhihao Ma,Shasha Zhang,Tianyue Guan,Jun Wang,Long Chen,Wanyi Xu,Hong Yu,Huizhen Chen,Jingquan Dong
Chronic intermittent hypoxia (CIH) caused by obstructive sleep apnea (OSA) exacerbates renal dysfunction, fibrosis, and chronic kidney disease (CKD) progression. This study investigates the renoprotective effects and mechanisms of atraric acid (AA), a natural compound from oakmoss with anti-inflammatory and antioxidant properties, against CIH-induced renal injury. A CIH mouse model was established, with groups including control, CIH, and CIH mice treated with AA (5, 10, 20 mg/kg). Mice underwent daily 8-h hypoxia exposure for 4 weeks. Renal pathology was assessed via HE and Masson staining, while fibrosis markers (α-SMA, collagen I, TGF-β1), oxidative stress (DHE staining, MDA levels), ferroptosis (iron content), and Nrf2/GPX4 pathway proteins were analyzed using biochemical assays and Western blotting. Results showed that AA treatment dose-dependently alleviated CIH-induced renal injury and fibrosis, reducing the expression of fibrotic proteins. AA suppressed ROS accumulation and lipid peroxidation while mitigating iron overload. Mechanistically, AA activated the Nrf2/Keap1 pathway, upregulating antioxidant proteins GPX4 and SLC7A11, thereby inhibiting oxidative stress and ferroptosis. These findings provide the first evidence that AA ameliorates CIH-related renal damage by targeting the Nrf2/GPX4 axis, offering a novel therapeutic strategy for CKD associated with OSA. The study highlights AA's potential in attenuating hypoxia-driven renal fibrosis through dual modulation of oxidative stress and ferroptosis pathways.
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FOLIA BIOLOGICA
·
2022
·Vol. 68
·期 2
·59-71
·
IF 1.167
Shao ZC,Zhu BH,Huang AF,Su MQ,An LJ,Wu ZP,Jiang YJ,Guo H,Han XQ,Liu CM
Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase- 3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT /Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 5
·
IF 5.6
Tong Chen,Jing Zhang,Shaoqin Jian,Bocen Chen,Yingjie Ma,Wenguang Wang,Tianpeng Ma,Jiran Shi,Jin Yang,Man Xiao
Paederia scandens(Lour.)Merris a substance exhibiting medicine–food homology (MFH), commonly used in China. However, the antioxidant and anti-aging effects ofpaederoside(PSG) have not been thoroughly investigated; therefore, in this study,Caenorhabditis elegans(C. elegans) was treated with PSG to investigate these effects. We found that 50, 80, and 100 μg/mL of PSG could prolong the lifespan ofC. elegans, and administration of 100 μg/mL PSG significantly reduced the accumulation of lipofuscin. Under conditions of oxidative stress, RT-qPCR analysis revealed that PSG treatment significantly up-regulated the expression of key antioxidant geneskn-1and longevity-associated genedaf-16. In addition, PSG increased the activity of the antioxidant enzymes SOD and CAT and reduced the level of MDA. When DAF-2 activity is reduced or inhibited inC. elegans, DAF-16 and SKN-1 are activated and translocate to the nucleus to promote stress resistance and prolong lifespan. Finally, by utilizing HeLa cell models, we demonstrated that the core component ofPaederia scandens, PSG, promotes targeted degradation of IGF1R through the ubiquitin–proteasome system. Our results suggest that feedingC. elegansPSG is effective in extending this organism’s lifespan by improving oxidative stress resistance; thus, PSG has significant potential for development as an anti-aging food product and drug.
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Antioxidants
·
2023
·Vol. 12
·期 1
·194
·
IF 7
Chongshan Dai,Xueyong Zhang,Jiahao Lin,Jianzhong Shen
Acute liver injury is a type of liver diseases, and it has raised concerns worldwide due to the lack of effective therapies. The aim of this study is to investigate the protective effects of nootkatone (NOOT) on carbon tetrachloride (CCl4)-caused acute liver injury in mice. Mice were randomly divided into control, CCl4model, NOOT, and NOOT (5, 10, and 20 mg/kg/day) plus CCl4groups, respectively. Mice in the CCl4plus NOOT groups were orally administrated with NOOT at 5, 10, and 20 mg/kg/days for seven days prior to 0.3% CCl4injection at 10 mL/kg body weight, respectively. Our results showed that NOOT supplementation significantly ameliorated CCl4-induced increases of serum AST and ALT levels, hepatocyte necrosis, inflammatory response, oxidative stress, and caspases-9 and -3 activities in the livers of mice. Moreover, NOOT supplementation significantly upregulated the expression of Nrf2 and HO-1 mRNAs but downregulated the expression of NF-κB mRNAs and the levels of IL-1β, IL-6, and TNF-α proteins in the liver tissues, compared to those in the CCl4model group. In conclusion, for the first time, our results reveal that NOOT could offer protective effects against CCl4-caused oxidative stress and inflammatory response via the opposite regulation of Nrf2/HO-1 pathway and NF-κB pathway.Keywords:nootkatone;oxidative stress;acute liver injury;Nrf2/HO-1 pathway;NF-κB pathway
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