JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2025
·Vol. 44
·期 1
·1-31
·
IF 12.8
Chang Chunxiao,Wang Meng,Li Jia,Qi Sihao,Yu Xiaojuan,Xu Jun,Shi Shengbin
Background Chronic liver injury is a key factor in diseases like hepatocellular carcinoma (HCC), steatohepatitis (NASH), and viral hepatitis type B and C (HBV, HCV). Understanding its molecular mechanisms is crucial for effective treatment. The NOTCH1 signaling pathway, though not fully understood, is implicated in liver injury and may be a potential therapeutic target.Methods Clinical HCC, HBV, HCV and NASH samples and additional in vitro and in vivo performances were subjected to confirm the role of NOTCH1 and its downstream targets via a series of biochemical assays, molecular analysis approaches and targeted signaling pathway assay, etc.Results The present study first verified the abnormal elevation of NOTCH1 in hepatocytes from patients with steatohepatitis, HCC, HBV, HCV, and mouse models. Crucially, we discovered that hepatocyte-specific NOTCH1 knockout reduces hepatocellular damage in chronic liver inflammation and HCC mouse models, whereas adeno-associated virus serotype 8 (AAV8)-mediated NOTCH1 overexpression in hepatocytes exacerbates liver injury-related phenotype on-setting. Mechanistically, we showed that NOTCH1 has a new role in controlling ferroptosis and oxidative damage in hepatocytes. It interacts with Kelch-like ECH-associated protein 1 (KEAP1) and is directly recruited through its intracellular domain (NICD1). Additionally, the KEAP1 recruited by NOTCH1 impeded the binding stability of KEAP1-NFE2 like BZIP transcription factor 2 (Nrf2), promote the separation of KEAP1 and Nrf2, thereby reducing the stability of Nrf2 and hindering the ubiquitination-related proteasome degradation of Nrf2. Crucially, we also discovered that NOTCH1’s ANK domain is essential for NICD1-KEAP1 contacts and signaling activation. The inability of NOTCH1 with ANK domain mutants (ΔANK) to connect with KEAP1 and increase its expression emphasizes the importance of the ANK domain in KEAP1-NRF2 signaling. By reversing the downregulation of KEAP1 and the overexpression of NRF2, ANK function is linked to ferroptosis and ROS buildup. ANK domain targeting may slow the course of HCC and liver damage.Conclusion sTargeting the NOTCH1-KEAP1-NRF2 axis as a possible chronic hepatic injury therapy is supported by these findings, which identify NOTCH1-KEAP1 as an NRF2 suppressor that accelerates the progression of liver injury.
研究领域:
分子生物学
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生物化学
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癌症生物学
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肝病学
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信号转导
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遗传学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Ning Li,Liuding Wen,Fangyu Wang,Tianlin Wang,Tiange Li,Mingwu Qiao,Lianjun Song,Erkigul Bukyei,Xianqing Huang
It is well known that lead-induced neurotoxicity is closely related to oxidative stress. According to previous reports, wheat germ peptides (WGPs) isolated from wheat germ have been shown to have potent antioxidant capacity. This study hypothesized that WGPs could protect PC12 cells from lead-induced oxidative stress. Here, the protecting-efficacies of WGPs were investigated in PC12 cells that were pretreated with WGPs (200 μM, 4 h) and exposed to lead (10 μM, 24 h). The antioxidant capacity was assessed by cell viability, ROS, MDA, SOD, CAT, GR, GPx, GSH, and GSSG. The experimental results showed that WGP3, WGP8, and WGP9 could reverse the reduction of cell viability caused by lead exposure. Lead exposure causes oxidative stress by increasing the levels of ROS and MDA. Moreover, the decrease in the levels of SOD, CAT, GPx, GR, and GSH/GSSG could be observed. However, WGP3, WGP8, and WGP9 can protect PC12 cells against lead-induced oxidative stress by reversing these phenomena. The protein expression of TXNIP, Keap1, and Nrf2 was characterized by western blotting, and the results illustrated that lead exposure up-regulated the expression of TXNIP and Keap1 and down-regulated the expression of Nrf2, and WGP3, WGP8, and WGP9 could improve the antioxidant capacity of PC12 cells by reversing this phenomenon. Therefore, the present study demonstrated that WGP3, WGP8, and WGP9 may protect against lead-induced oxidative stress in PC12 cells by regulating the TXNIP/Keap1/Nrf2 pathway.
研究领域:
神经毒理学
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氧化应激
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细胞生物学
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药理学
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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
FOOD CHEMISTRY
·
2025
·
IF 9.8
Huan-Huan Xiao,Xue-Ying Li,Ying-Ying Chen,Jin-Xiang Zhou,Ting Zhang,Qiang-Ming Li,Li-Hua Pan,Jian-Ping Luo,Xue-Qiang Zha
The aim of this study was to identify novel antioxidant peptides from quinoa ( Chenopodium quinoa wild.) protein hydrolysates, which were prepared using enzyme combination methods. Eleven novel antioxidant peptides were screened through in silico evaluation, and their structure-activity relationships were further investigated. Molecular docking studies indicated that GPGGGGKGEMF (GF-11) exhibited a higher binding affinity and interaction capacity. GF-11 significantly reduced reactive oxygen species (ROS) levels to 43.20 and malondialdehyde (MDA) levels to 1.92 nmol/mg protein in oxidatively damaged RAW264.7 cells, while also significantly enhancing SOD, GSH-Px, and CAT activities to 25.33, 133.99, and 43.20 U/mg protein, respectively. Furthermore, GF-11 competed with Nrf2 for the binding site on Keap1, promoting the expression of Nrf2, HO-1, and NQO1 proteins, which ultimately activated the Keap1-Nrf2 pathway and mitigated oxidative damage. These findings provide a scientific basis for the application of quinoa antioxidant peptides in the development of functional foods.
研究领域:
食品科学
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分子生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 20
·12086
·
IF 6.208
Jiaojiao Zhang,Shaozhen Wu,Qingqing Wang,Qinjie Yuan,Yane Li,Patricia Reboredo-Rodríguez,Alfonso Varela-López,Zhiping He,Fenghua Wu,Hao Hu,Xingquan Liu
Pecan (Carya cathayensis) is an important economic crop, and its hydrolyzed peptides have been evidenced to reduce the effect of oxidative stress due to their antioxidant capacity. Hence, the protocols of ultrafiltration and gel filtration chromatography were established to obtain bioactive peptides from by-products ofC. cathayensis(pecan cake). As measured by DPPH/ABTS radical scavenging, the peptides with less molecular weight (MW) possess higher antioxidant capacity. PCPH-III (MW < 3 kDa) presented higher radical scavenging capacity than PCPH-II (3 kDa < MW < 10 kDa) and PCPH-I (MW > 10 kDa) measured by DPPH (IC50: 111.0 μg/ mL) and measured by ABTs (IC50: 402.9 μg/mL). The secondary structure and amino acid composition varied by their MW, in which PCPH-II contained more α-helices (26.71%) and β-sheets (36.96%), PCPH-III contained higher ratios of β-turns (36.87%), while the composition of different secondary of PCPH-I was even 25 ± 5.76%. The variation trend of α-helix and random experienced slightly varied from PCPH-I to PCPH-II, while significantly decreased from PCPH-II to PCPH-III. The increasing antioxidant capacity is followed by the content of proline, and PCPH-III had the highest composition (8.03%). With regard to the six peptides identified by LC-MS/MS, two of them (VYGYADK and VLFSNY) showed stronger antioxidant capacity than others. In silico molecular docking demonstrated their combining abilities with a transcription factor Kelch-like ECH-associated protein 1 (Keap1) and speculated that they inhibit oxidative stress through activating the Keap1-Nrf2-ARE pathway. Meanwhile, increased activity of SOD and CAT—antioxidant markers—were found in H2O2-induced cells. The residue of tyrosine was demonstrated to contribute the most antioxidant capacity of VYGYADK and its position affected less. This study provided a novel peptide screening and by-product utilization process that can be applied in natural product developments.Keywords:Chinese pecan by-products;antioxidant peptides;proline content;molecular docking;Keap1-Nrf2-ARE pathway
研究领域:
食品科学
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生物化学
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药理学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Lang Liu,Jingyu Weng,Lei Yue,Yuanyuan Qin,Jia Yu,Yaqi Li,Shuming Li,Jiaofeng Wu,Yuangui Yang,Zhishu Tang,Hongbo Xu
Cerebral ischemia–reperfusion injury exacerbates neuronal loss following acute ischemic stroke through oxidative stress and regulated cell-death pathways, notably ferroptosis. Here, we investigated whether rosmarinic acid (RA), a natural polyphenol, confers neuroprotection by inhibiting ferroptosis via activation of the KEAP1–NRF2 axis. In vivo , rats pretreated with RA (30 or 60 mg/kg, i.p.) for 14 days before middle cerebral artery occlusion/reperfusion exhibited dose-dependent improvements in neurological scores, reduced infarct volumes, preserved cerebral blood flow, and attenuated histopathological damage. In vitro , RA (25–50 μM) restored the viability of HT22 and PC12 cells subjected to oxygen-glucose deprivation/reperfusion, suppressed lipid reactive oxygen species accumulation, iron overload, and mitochondrial ultrastructural collapse. Mechanistically, RA promoted nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, enhanced antioxidant response element -driven luciferase activity, and upregulated ferroptosis-defense genes ( Gpx4 , Slc7a11 , and Gclm ) at both mRNA and protein levels. Cycloheximide chase and ubiquitination assays, supported by molecular docking, molecular dynamics simulations, and surface plasmon resonance, demonstrated that RA directly binds Kelch-like ECH-associated protein 1 (KEAP1) to stabilize NRF2. A KEAP1 knockdown abolished RA's induction of NRF2 targets and its anti-ferroptotic effects. These findings establish RA as a targeted NRF2 activator and ferroptosis inhibitor, offering a promising therapeutic strategy for limiting ischemia–reperfusion-induced neuronal injury.
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PubMed
高影响因子
Food & Function
·
2025
·
IF 5.4
Jiaxuan Li,Yu Li,Xunyu Song,Yuxiao Wang,Yinxu Zhang,Xinghua Gao,Mingqian Tan,Wentao Su
High-fat diets (HFDs) impair the intestinal barrier by increasing permeability and oxidative stress, which contributes to obesity-related disorders. Ulva lactuca, a marine green alga, produces extracellular vesicles (UEVs) that remain underexplored as functional food components. In this study, UEVs were isolated and characterized, showing a cup-like shape morphology with average diameter of 188.8 nm. Functional assays demonstrated that UEV treatment attenuated oxidative stress, reduced apoptosis, and restored tight junction proteins. In a gut-on-a-chip model, UEVs improved transepithelial electrical resistance (TEER) and enhanced mucin secretion under HFD-mimicking stress. Mechanistic studies revealed that UEVs activated the Nrf2/Keap1/HO-1 signaling pathway, promoting nuclear translocation of Nrf2 and upregulation of antioxidant genes. Collectively, these findings highlight UEVs as novel food-derived nanostructures with dual functions in oxidative stress reduction and intestinal barrier protection, supporting their potential in functional food applications targeting metabolic gut disorders.
研究领域:
海洋生物学
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营养科学
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分子生物学
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纳米技术
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
HISTOLOGY AND HISTOPATHOLOGY
·
2026
·Vol. 41
·期 3
·453-465
·
IF 2.2
Xuefei Fan,Suhuan Chen,Haomiao Liu,Nannan Liu,Mengyan Zhang,Mengmeng Chen,Wuqi Chen,Guangyi Chen,Weilu Gao,Tao Yao,Xiaoyu Chen
Background: Rheumatoid arthritis can affect extra-articular organs such as the liver, and the problem of drug-induced liver injury caused by traditional antirheumatic drugs for improving the condition cannot be ignored. This study aims to investigate the therapeutic effects of resveratrol (Res) on hepatic inflammation and oxidative stress in mice with collagen-induced arthritis (CIA) and to elucidate the relationship between the regulatory mechanisms of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway. Methods: In this study, we used chicken type II collagen in combination with complete Freund's adjuvant to induce arthritis in a mouse model, and Res was administered by tube feeding to detect the serum biochemical liver function and inflammation levels, oxidative stress, and apoptosis in the livers of mice. An in vitro cellular model of liver inflammation and oxidative stress was established by treating mouse primary hepatocytes (MPHs) with tumor necrosis factor-α (TNF-α) and H 2 O 2 . The intrinsic mechanism of Res in attenuating hepatic inflammation and oxidative stress in CIA mice was explored by treating MPHs with an Nrf2 inhibitor and Keap1 overexpression plasmid. Results: Res significantly reduced the levels of inflammation and oxidative stress in liver tissues of CIA mice as well as in MPHs treated with TNF-α and H 2 O 2 and activated the Nrf2/Keap1 signaling pathway. Inflammation and oxidative stress levels in MPHs were exacerbated by the use of Nrf2 inhibitors and Keap1 overexpression, which promoted apoptosis. Conclusion: This study demonstrated the intrinsic mechanism of Res of attenuating hepatic inflammation and oxidative stress in CIA mice through the Nrf2/Keap1 pathway, which provides a new idea for finding hepatoprotective treatments for rheumatoid arthritis.
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PubMed
高影响因子
Frontiers in Immunology
·
2026
·
IF 7
Jinli Ma,Luya Pu,Yundong Zhang,Baiao Wu,Rui Fei,Dongmei Han,Miao Hao,Jianshi Du
BackgroundSecondary lymphedema leads to progressive tissue remodeling and immune dysregulation. Dysregulation of macrophage polarization critically influences pathological progression. Oxidative stress and mitochondrial homeostasis are the critical components of secondary lymphedema.MethodsA secondary lymphedema model and an LPS-induced in vitro cell injury model were established. Mitochondrial dynamics were evaluated using the ROS assay, mitochondrial membrane potential analysis and mPTP opening assays. Mechanistic investigations included Nrf2 nuclear translocation analysis via immunofluorescence, western blotting, and pharmacological inhibition of exosome biogenesis using GW4869.ResultsSecondary lymphedema tissues exhibited a significant imbalance in M1/M2 macrophage infiltration (with an increase in M1 and decrease in M2), along with elevated IL-1β levels. M2-Exo significantly prevents the proliferation, migration, and tube formation of human lymphatic endothelial cells and alleviated the mitochondrial damage induced by LPS. This mechanism may involve activation of Keap1-Nrf2 signaling.ConclusionM2 macrophage exosomes activated the Nrf2 anti-oxidative stress pathway. This activation improves mitochondrial homeostasis and enhances the function of human lymphatic endothelial cells by delivering active ingredients, offering a new strategy for the treatment of secondary lymphedema.
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2019
·
IF 3.407
Jialin Xu,Leilei Zhou,Qi Weng,Linxia Xiao,Qingyong Li
Beta-amyloid (Aβ) has pivotal functions in the pathogenesis of Alzheimer's Disease (AD). In the present study, we adopted an vitro model that involved Aβ 25-35 -induced oxidative damage in PC12 cells. Aβ 25-35 (10 μΜ) treatment for 24 h induced significant cell death and oxidative stress in PC12 cells, as evidenced by cell viability reduction, LDH release, ROS accumulation and increased production MDA . (1E,4E)-1, 5-bis(4-hydroxy-3-methoxyphenyl) penta-1, 4-dien-3-one (CB) and (1E, 4E)-1-(3, 4-dimethoxyphenyl)-5-(4-hydroxy-3, 5-dime-thoxyphenyl) Penta-1, 4-dien-3-one (FE), two Curcumin (Cur) analogues displayed neuroprotective effects against Aβ 25-35 -induced oxidative damage and cellular apoptosis in PC12 cells. Here, we investigated three different treatment ways of CB and FE. It was interesting that post-treatment of CB and FE (restoring way) showed similar effect to the preventive way, while attenuating way did not show any protective effect. We found that low dose CB and FE increased transcriptional factor NF-E2-related factor 2 (Nrf2)/hemo oxygenase 1 (HO-1) protein expression and decreased Kelch-like ECH-associated protein 1 (Keap1) in PC 12 cells. In addition, CB and FE promoted the translation of Nrf2 into nuclear and enhanced the activity of superoxide dismutase (SOD)/catalase, which confirmed cytoprotection against Aβ 25-35 -induced oxidative damage. Moreover, CB and FE could increase Bcl-2 expression level, decrease the level of Bax and Cyt-c in Aβ 25-35 -treated PC12 cells. Ultimately, the neuroprotective effect of CB and FE provides a pharmacological basis for its clinical use in prevention and treatment of AD.
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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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Na Li,Hehe Shi,Wei Du,Siqian Luo,Xianyue Yang,Xinyue Yang,Bingyue Jiang,Peng Xia,Guangji Zhang,Wanghui Jing
The progression from ulcerative colitis to colitis-associated colorectal cancer (CAC) represents a significant clinical challenge. 6-Shogaol, a bioactive phenolic compound of ginger, exhibits anti-inflammatory, antioxidant, and anti-tumor properties. This study aims to investigate the therapeutic efficacy of 6-shogaol against colitis and CAC, and explore the underlying mechanisms through network pharmacology and in vivo validation. Putative hub targets and pathways associated with 6-shogaol were identified through network pharmacology. Murine models of dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-induced CAC were established, and the mice were treated with 6-shogaol to assess the latter’s therapeutic effects. The targets of 6-shogaol predicted through network pharmacology were mainly associated with oxidative stress and reactive oxygen species (ROS) signaling pathways. I n vivo , 6-shogaol relieved colitis symptoms and reduced CAC tumor burden. Furthermore, 6-shogaol alleviated intestinal inflammation by decreasing the colonic levels of TNF-α and MPO, and reduced oxidative stress in the colon tissues, as indicated by lower ROS production and malondialdehyde content. Moreover, 6-shogaol restored intestinal barrier function by upregulating claudin-4, occludin, and ZO-1, and decreasing intestinal permeability. Mechanistically, 6-shogaol promoted Nrf2 nuclear translocation by upregulating nuclear Nrf2 expression while downregulating cytoplasmic Keap1, thereby activating antioxidant response element driver genes, including Hmox1 , Nqo1 , and Gclc . Molecular docking confirmed strong binding affinity between 6-shogaol and Keap1 receptor, with a low binding energy of -6.89 kcal/mol. These findings collectively suggested that 6-shogaol alleviated colitis and CAC in murine models by inhibiting colonic inflammation, relieving oxidative stress, and enhancing intestinal barrier function through the activation of the Nrf2-Keap1 pathway.
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PubMed
高影响因子
EXPERIMENTAL BIOLOGY AND MEDICINE
·
2023
·
IF 3.2
Jinhong Tian,Shuaishuai Zhang,Lu Li,Xueman Lin,Yongmei Li,Kunlu Zhao,Fengxin Zheng,Yongjun Chen,Yang Yang,Ting Wu,Jianxin Pang
Excessive acetaminophen (APAP) application is a major cause of drug-induced liver injury (DILI). Febuxostat (Feb), a drug for reducing uric acid (UA) levels, was demonstrated to relieve hepatic inflammation and reverse organ functions. However, the effect of Feb on APAP-induced DILI and its mechanisms have not been fully explored. In this study, Feb (10 mg/kg) was given to mice by gavage 1 h after APAP (300 mg/kg, i.g.) induction. Serum and liver samples were collected 12 or 3 h after APAP challenge. Feb treatment was found to remarkably improve APAP-induced DILI, as evidenced by reduced serum ALT, AST and UA levels, pathomorphology, inflammatory, and oxidative responses. Consistently, treatment with Feb also reduced the cell injury induced by APAP in LO2 cells. Mechanistically, Feb induced GPX4 expression, activated the Keap1/Nrf2 pathway, and inhibited the TLR4/NF-κB p65 pathway. Feb also inhibited glutathione (GSH) depletion and Jun N-terminal kinase (JNK) activation in the early injury phase. Notably, pretreatment with Feb for 3 days also revealed preventive effects against APAP-induced DILI in mice. Overall, our data revealed a potential health impact of Feb on APAP-mediated DILI in vivo and in vitro, suggesting that Feb might be a potential candidate for treating DILI.
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高影响因子
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