CELL BIOCHEMISTRY AND BIOPHYSICS
·
2025
·
IF 2.5
Xiang Ming,Lin Xiangdong,Chen Haiying
Coronary heart disease (CHD) is a disease caused by organic and functional coronary artery stenosis, resulting in a reduced oxygen supply to the heart. This study aimed to investigate the mechanism via which Luteolin regulates the Sirt1 / Nrf2 pathway to inhibit ferroptosis in human umbilical vein endothelial cells (HUVEC) associated with CHD. An ox-LDL-induced HUVEC cell model with Sirt1 silencing and Luteolin treatment was established. The silencing efficiency of Sirt1 was validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. The results of molecular docking and DARTS experiments showed that Luteolin could effectively bind Sirt1 . Subsequently, we measured the expression of Nrf2 and Sirt1 , cell viability, MDA, GSH, Fe 2+ levels, lipid ROS content, expression of ferroptosis-related proteins GPX4, FTH, FTL, and cell migration parameters. The results showed that Luteolin could activate the Sirt1 / Nrf2 axis and effectively inhibit ox-LDL-induced ferroptosis in HUVEC. Experimental results revealed that Luteolin could enhance HUVEC cell viability, decrease MDA, Fe 2+ , and ROS levels, increase GSH levels, promote the expression of HO-1, GPX4, FTH, FTL, inhibit the expression of ACSL4 and TFRC, and enhance the migration capability of HUVEC cells. Moreover, silencing Sirt1 reversed the effects of Luteolin on the activation of Sirt1 and Nrf2 , confirming the dependence of these effects on the Sirt1 / Nrf2 signaling pathway. In conclusion, this study indicates that Luteolin could inhibit ferroptosis in HUVEC in CHD by modulating the Sirt1 / Nrf2 axis, providing a basis for further research on strategies for preventing and treating CHD and related diseases.
研究领域:
药理学
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分子生物学
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心脏病学
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
CURRENT MOLECULAR MEDICINE
·
2023
·
IF 2.5
Wang Qi,Zhang Aihua
Background: Oxidative stress is a key mechanism underlying arsenicinduced
liver injury, the Kelch-like epichlorohydrin-related protein 1 (Keap1)/nuclear
factor E2 related factor 2 (Nrf2) pathway is the main regulatory pathway involved in
antioxidant protein and phase II detoxification enzyme expression. The aim of the present
study was to investigate the role and mechanism of baicalein in the alleviation of
arsenic-induced oxidative stress in normal human liver cells.
Methods: Normal human liver cells (MIHA cells) were treated with NaAsO2 (0, 5, 10,
20 μM) to observe the effect of different doses of NaAsO2 on MIHA cells. In addition,
the cells were treated with DMSO (0.1%), NaAsO2 (20 μM), or a combination of NaAsO2
(20 μM) and Baicalein (25, 50 or 100 μM) for 24 h to observe the antagonistic effect
of Baicalein on NaAsO2. Cell viability was determined using a Cell Counting Kit-8
(CCK-8 kit). The intervention doses of baicalein in subsequent experiments were determined
to be 25, 50 and 100μM. The intracellular content of reactive oxygen species
(ROS) was assessed using a 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA)
probe kit. The malonaldehyde (MDA), Cu-Zn superoxide dismutase (Cu-Zn SOD) and
glutathione peroxidase (GSH-Px) activities were determined by a test kit. The expression
levels of key genes and proteins were determined by real-time fluorescence
quantitative polymerase chain reaction (qPCR) and Western blotting.
Results: Baicalein upregulated the protein expression levels of phosphorylated Nrf2
(p-Nrf2) and nuclear Nrf2, inhibited the downregulation of Nrf2 target genes induced by
arsenic, and decreased the production of ROS and MDA. These results demonstrate
that baicalein promotes Nrf2 nuclear translocation by upregulating p-Nrf2 and inhibiting
the downregulation of Nrf2 target genes in arsenic-treated MIHA cells, thereby enhancing
the antioxidant capacity of cells and reducing oxidative stress.
Conclusion: Baicalein alleviated arsenic-induced oxidative stress through activation
of the Keap1/Nrf2 signalling pathway in normal human liver cells.
研究领域:
毒理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Redox Biology
·
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.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
·
IF 3.831
Zhang Man,Wu Yan-Qing,Xie Ling,Wu Jiang,Xu Ke,Xiao Jian,Chen Da-Qing
Severe acute pancreatitis (SAP) is a digestive system disease that is associated with a range of complications including intestinal dysfunction. In this study, we determined that the chalcone compound, isoliquiritigenin (ISL), reduces pancreatic and intestinal injury in a mouse model of SAP. These effects were achieved by suppressing oxidative stress and the inflammatory responses to SAP. This was evidenced by a reduction in histological score, and malondialdehyde (MDA), interleukin (IL)-6, tumor necrosis factor (TNF)-α and cleaved-caspase-3 (c-caspase-3) protein along with an increase in Nrf2, hemeoxygenase-1 (HO-1), quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD). We then used Nrf2-/- mice to test the protective effect of Nrf2 during ISL treatment of SAP. Our results indicated that Nrf2-/- mice had greater pancreatic injury and intestinal dysfunction than wild-type mice. They also had reduced adherens junctions (P120-catenin) and tight junctions (occludin), and increased activated nuclear factor-κB (NF-κB) protein. In Nrf2-/- mice, ISL was less effective at these functions than in the WT mice. In conclusion, this study demonstrated that ISL exerts its protective effects against oxidative stress and inflammatory injury after SAP via regulation of the Nrf2/NF-κB pathway. It also showed that the efficacy of ISL in repairing the intestinal barrier damage caused by SAP is closely related to the Nrf2 protein. Our findings demonstrated that Nrf2 is an important protective factor against SAP-induced injuries in the pancreas and intestines.
研究领域:
药理学
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胃肠病学
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
Translational Cancer Research
·
2025
·Vol. 14
·期 11
·7641
·
IF 1.7
Yuan Cheng,Liu Ruiwen,Xu Xinming,Sun Jun,Zhu Yi,Lu Rongzhu,Liu Yueyu,Chen Jian
Background Because of the high malignancy and subtle early symptoms of hepatocellular carcinoma (HCC), most patients lose the opportunity for surgery and opt for drug therapy. However, the current drugs for HCC treatment remain suboptimal, underscoring the urgent need to develop a novel anti-HCC agent. Curcumin is a natural chemical compound that has anti-cancer effects on various tumor cells, attracting sustained attention from researchers and clinicians. The present study aims to further elucidate curcumin’s anti-HCC mechanisms, thereby offering a promising therapeutic candidate for HCC patients. Methods The viability of HCC cells was evaluated by Cell Counting Kit-8 (CCK-8) assay. The levels of glutathione (GSH), malondialdehyde (MDA), and total iron in the cells were detected by biochemical kits. The levels of reactive oxygen species (ROS) and Fe 2+ in the cells were detected by fluorescent probes. The protein expressions of protein kinase RNA-like endoplasmic reticulum kinase (PERK), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) in the cells were detected by western blotting. Results Curcumin exerted a notably suppressive impact on HCC cells, which could be reversed by ferrostatin-1 (Fer-1) and desferrioxamine (DFO). By detecting cellular metabolic products, we observed an increase in total iron, Fe 2+ , MDA, ROS, and a reduction in GSH levels in HCC cells after treatment with curcumin, and these effects could be attenuated by Fer-1. Western blot analysis showed that curcumin significantly downregulated GPX4 levels in HCC cells while upregulating PERK, Nrf2 and HO-1 expression. Additionally, using PERK inhibitor, HO-1 inhibitor, and endoplasmic reticulum (ER) stress inhibitor could partially reverse the inhibition of HCC cells viability by curcumin and alleviate the reduction of GPX4 expression caused by curcumin. Conclusions Curcumin may induce ferroptosis in HCC cells through the PERK/Nrf2/HO-1 signaling pathway, thereby exerting its anti-cancer effects, suggesting that curcumin could potentially be used as a drug for treating HCC.
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2019
·
IF 3.571
Yanan Hou,Xinming Li,Shoujiao Peng,Juan Yao,Feifei Bai,Jianguo Fang
The mechanisms underlying neurodegenerative diseases are not fully understood yet. However, an increasing amount of evidence has suggested that these disorders are related to oxidative stress. We reported herein that lipoamide (LM), a neutral amide derivative of lipoic acid (LA), could resist oxidative stress-mediated neuronal cell damage. LM is more potent than LA in alleviating hydrogen peroxide- or 6-hydroxydopamine-induced PC12 cell injury. Our results reveal that LM promotes the nuclear accumulation of NFE2-related factor 2 (Nrf2), following with the activation of expression of Nrf2-governed antioxidant and detoxifying enzymes. Notably, silencing Nrf2 gene annuls the protection of LM, which demonstrates that Nrf2 is engaged in this cytoprotection. Our findings suggest that LM might be used as a potential therapeutic candidate for oxidative stress-related neurological disorders.
研究领域:
神经科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2025
·Vol. 20
·期 3
·e0310879
·
IF 2.6
Yao Dong,Ru Jia,Yujie Jiang,Qing Li,Lei Wang,Wensi Ding,Rui Yan,Yujie Qiu,Zhengjie Shi,Wenying Liu,Jing Wang,Sen Xu,Na Li
Background
Acetaminophen (APAP) can be used for pain relief and fever alleviation, the overdose of which, however, may lead to the accumulation of N-acetyl-p-benzoquinone imine (NAPQI), inducing oxidative stress and liver damage. The natural compound SMND-309 has been shown to have hepatoprotective effects and potential antioxidant activity. However, its ability to alleviate acetaminophen-induced acute liver injury (AILI) has not been elucidated.
Objective
To explore the protective effect of the natural compound SMND-309 against AILI and the potential mechanism.
Methods
The AILI model was established using a mouse model and HepG2 cells for pathological evaluation and biochemical assays of mouse liver tissues to assess the level of liver injury. The effects of SMND-309 on cellular ROS levels and mitochondrial membrane potential were detected using DCFH-DA and JC-1 probes. Western blotting was performed to detect the expressions of Nrf2 signaling pathway and key proteins related to APAP metabolism in the combination of immunohistochemistry of liver tissues, with immunofluorescence assay used to detect whether Nrf2 undergoes nuclear translocation. Molecular docking, molecular dynamics simulation (MD) and biofilm layer interference (BLI) experiments were performed to detect the interaction of SMND-309 with Keap1.
Results
SMND-309 improved histopathological changes in the liver, decreased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels, as well as attenuated oxidative stress injury and mitochondrial dysfunction in the HepG2 cell line. Further studies revealed that SMND-309 promoted nuclear translocation of Nrf2 and upregulated the expressions of glutamate-cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). In addition, molecular docking and MD suggested that SMND-309 could bind Keap1 and identified possible binding modes, with BLI experiments confirming that SMND-309 directly interacted with Keap1.
Conclusion
SMND-309 exerts hepatoprotective effects against AILI in an Nrf2-ARE signaling pathway-dependent manner.
研究领域:
药理学
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肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Veterinary Science
·
2025
·
IF 2.9
Baili Lu,Jiayu He,Shirou Pan,Junhao Wei,Bingxin Li,Nan Cao,Yunmao Huang,Yunbo Tian,Ngai Cheong,Ying Chen,Danning Xu,Wanyan Li
Atractylodes macrocephala Koidz. (AMK) and its purified polysaccharide fraction (PAMK) are known for their antioxidant, anti-inflammatory, and hepatoprotective properties, showing potential benefits for poultry liver health. This study simulated hepatic oxidative stress in late-laying hens, a physiological stage characterized by increased metabolic demands and reactive oxygen species (ROS) generation, without exogenous hepatotoxic agents. Hens were randomly assigned to three groups: control (basal diet), AMK (basal diet + 15 g/kg AMK), and PAMK (basal diet + 400 mg/kg PAMK). Both AMK and PAMK significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities compared to control. Notably, PAMK showed superior efficacy, decreasing malondialdehyde (MDA) levels by 35.29% vs. 32.87% in AMK, and more effectively increasing antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Histopathological analysis revealed better-preserved liver structure and less inflammatory infiltration in PAMK-fed hens. Mechanistically, both treatments upregulated Nrf2 and downstream antioxidant genes, with stronger activation observed in the PAMK group. In vitro, PAMK reduced H2O2-induced ROS accumulation and apoptosis in primary embryonic chicken hepatocytes, effects that were attenuated by the Nrf2 inhibitor ML385. In conclusion, PAMK exerts superior hepatoprotective effects compared to crude AMK by modulating the Nrf2 pathway, mitigating oxidative stress, apoptosis, and autophagy. Future research should evaluate PAMK's long-term safety, synergistic potential with other natural antioxidants, and cost-effectiveness in poultry production.
研究领域:
兽医学
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动物营养学
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分子生物学
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氧化应激
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天然药物药理学
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家禽生理学
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产品关联
DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Jianfa Wu,Lingjie Bao,Zhenbo Zhang,Xiaofang Yi
Induction of Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) has been demonstrated to be involved in cisplatin resistance in ovarian cancer. Solute carrier family 40 member 1 (SLC40A1) is an iron exporter, which possesses many putative Nrf2 binding sites. Here we hypothesize that it may be a possible downstream gene of Nrf2. Elevated level of Nrf2 and reduced level of SLC40A1 were found in cisplatin–resistant ovarian cancer cells as compared with cisplatin-sensitive ovarian cancer cells. Exogenous knockdown of Nrf2 leaded to increased expression of SLC40A1. While overexpression of Nrf2 resulted in decreased expression of SLC40A1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay revealed that Nrf2 inhibited the transcription of SLC40A1. Overexpression of SLC40A1 was able to reverse cisplatin resistance induced by Nrf2, while knockdown of SLC40A1 restored cisplatin resistance and increased iron concentration. Desferal, an iron chelator, was found to overcome cisplatin resistance through iron deprivation. Its function was boosted when combined with brusatol, an Nrf2 inhibitor. Taken together, this study first demonstrated that Nrf2 could transcriptionally suppress the expression of SLC40A1. Iron overload induced by SLC40A1 resulted in cisplatin resistance in ovarian cancer. Targeting iron metabolism may be a new therapeutic strategy to reverse drug resistance in ovarian cancer treatment.
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
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2018
·Vol. 22
·期 7
·3514-3525
·
IF 4.302
Wenhui Cui,Zhihui Zhang,Panpan Zhang,Jiao Qu,Cheng Zheng,Xiaoting Mo,Wencheng Zhou,Liang Xu,Hongwei Yao,Jian Gao
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and abnormal inflammatory response. Wnt/β-catenin and AMP-activated protein kinase (AMPK) have been shown to modulate lung inflammatory responses and injury. However, it remains elusive whether Wnt/β-catenin and AMPK modulate nuclear factor erythroid-2 related factor-2 (Nrf2)-mediated protective responses during the development of emphysema. Here we showed that treatment with a Wnt pathway activator (LiCl) reduced elastase-induced airspace enlargement and cigarette smoke extract (CSE)-induced lung inflammatory responses in WT mice, which was associated with increased activation of Nrf2 pathway. Interestingly, these effects of LiCl were not observed in Nrf2 −/− mice exposed to elastase. In normal human bronchial epithelial (NHBE) cells, Wnt3a overexpression up-regulated, whereas Wnt3a knockdown further down-regulated the levels of Nrf2 and its target proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) by CSE treatment. In contrast, Nrf2 deficiency did not have any effects on Wnt/β-catenin pathway in mouse lungs and NHBE cells. Both elastase and CSE exposures reduced AMPK phosphorylation. A specific AMPK activator metformin increased Wnt3a, β-catenin, Nrf2 phosphorylation and activation but reduced the levels of IL-6 and IL-8 in NHBE cells and mouse lungs exposed to CSE. Furthermore, Nrf2 deficiency abolished the protection of metformin against CSE-induced increase in IL-6 and IL-8 in NHBE cells. In conclusion, Nrf2 mediates the protective effects of both Wnt3a/β-catenin and AMPK on lung inflammatory responses during the development of COPD/emphysema. These findings provide potential therapeutic targets for the intervention of COPD/emphysema.
研究领域:
医学
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分子生物学
·
药理学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Zaiwei Fan,Jianyuan Gao,Yikun Chen,Qirui Chen,Qingshan Peng,Jiadi Le,Yiming Li,Chunhui Chen,Haihong Jiang,Jun Tao,Yang Zhou
Osteoarthritis (OA) is a common degenerative joint disease featuring extracellular matrix degradation and apoptosis in the inflammatory microenvironment. Psoralea, a traditional Chinese herb derived from the dried and ripe fruits of the leguminous plant Psoralea corylifolia , possesses anti-inflammatory and antioxidant properties relying on the expression upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). Psoralen, a compound derived from Psoralea, can be well applied to the treatment of various diseases, while researches have not fully explored its therapeutic effect for OA. Our study aimed to conduct in vivo and in vitro experiments to investigate such effect. According to In vitro experiments, psoralen inhibited interleukin-6-induced chondrocyte inflammation and matrix metalloproteinase 13 production, meanwhile promoting aggrecan and type II collagen to be produced. Mechanistically, psoralen activated the Keap1/ Nrf2/ARE signaling pathway to enhance the antioxidant capacity of chondrocytes. Furthermore, in vivo experiments demonstrated the protective effect of psoralen against OA pathogenesis triggered by destabilized medial meniscus. Collectively, psoralen is considered as a potential candidate specific to OA treatment.
研究领域:
医学
·
生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Gao Ping,Du Xiaoyi,Liu Lili,Xu Hua,Liu Maochang,Guan Xinlei,Zhang Chengliang
Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the Astragalus which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-β1, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.
研究领域:
药理学
·
肾病学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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