BIOMACROMOLECULES
·
2023
·
IF 6.2
Dongdong Wang,Mu Li,Hanning Zhang,Congshu Feng,Lili Wu,Lesan Yan
Stimuli-responsive polymer nanocarriers, capable of exploiting subtle changes in the tumor microenvironment for controlled drug release, have gained significant attention in cancer therapy. Notably, NAD(P)H: quinone oxidoreductase 1 (NQO1), found to be upregulated in various solid tumors, represents a promising therapeutic target due to its effective capability to enzymatically reduce trimethyl-locked (TML) benzoquinone structures in a physiological condition. In this study, a novel redox-sensitive carbonate monomer, MTC, was synthesized, and its amphiphilic block copolymers were prepared through ring-opening polymerization. By successfully self-assembling poly(ethylene glycol)-b-PMTC micelles, the model drug doxorubicin (DOX) was encapsulated with high efficiency. The micelles exhibited redox-responsive behavior, leading to rapid drug release. In vitro assessments confirmed their excellent biocompatibility and hemocompatibility. Furthermore, the inhibition of the NQO1 enzyme reduced drug release in NQO1-overexpressed cells but not in control cells, resulting in decreased cytotoxicity in the presence of NQO1 enzyme inhibitors. Overall, this study showcases the potential of MTC-based polycarbonate micelles to achieve targeted and specific drug release in the NQO1 enzyme-mediated tumor microenvironment. Therefore, the self-assembly of MTC-based polymers into nanomicelles holds immense promise as intelligent nanocarriers in drug delivery applications.
研究领域:
生物医学工程
·
癌症治疗
·
材料科学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 4.7
Gao Jie,Lv Xiaoyu,Zhao Pingping,Pan Bingjing,Liu Jingfang
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes. The glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide exerts renoprotective effects beyond glucose control; however, the underlying mechanisms remain incompletely understood. The protective effects and mechanisms of liraglutide were investigated using in vitro (HK-2 cells under glucolipotoxic conditions) and in vivo (DKD rat) models. Key molecular and functional assessments included the evaluation of oxidative stress, apoptosis, mitochondrial function (dynamics (MFN1, MFN2, FIS1, and DRP1), mitophagy (PINK1, PARKIN, LC3II/I, and P62), and ultrastructure), and histone acetylation (H3K9/14/18/27ac). The critical role of the NQO1/SIRT3 pathway was validated using pharmacological inhibition and genetic silencing (shRNA/AAV). Both in vitro and in vivo, a multifaceted injury phenotype, including oxidative stress, apoptosis, mitochondrial dysfunction, and histone hyperacetylation, was induced, accompanied by downregulation of the NQO1/SIRT3 pathway. Disruption of this pathway further exacerbated these injuries. Conversely, liraglutide treatment effectively counteracted this phenotype, improving metabolic parameters (blood glucose, blood insulin, and blood lipids), renal function (blood urea nitrogen, serum creatinine, and urine albumin-to-creatinine ratio) and histopathology. Liraglutide attenuated oxidative stress and apoptosis, restored mitochondrial function and mitophagy, and reduced histone hyperacetylation. These protective effects were consistently associated with the restoration of NQO1/SIRT3 expression. Genetic or pharmacological disruption of the NQO1/SIRT3 axis significantly attenuated the efficacy of liraglutide, and combined inhibition completely abolished its effects. Our findings demonstrate that liraglutide attenuates DKD by activating the NQO1/SIRT3 pathway, which coordinates the enhancement of mitochondrial function and the restoration of epigenetic homeostasis. This study revealed that the NQO1/SIRT3 pathway is a critical mechanistic mediator of the renoprotective effect of liraglutide.
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高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2026
·
IF 3.5
Chenghao He,Jiaxin Jiang,Shuguang Hou,Runchun Xu,Qinwan Huang
Perfluorohexanesulfonic acid (PFHxS), a prevalent short-chain per- and polyfluoroalkyl substance, has been implicated in hepatocellular carcinoma (HCC), but mechanisms remain unclear. We integrated transcriptomic analyses of The Cancer Genome Atlas (TCGA) liver cancer cohort and an HCC single-cell dataset with molecular docking and molecular dynamics simulations and in vitro assays to examine a PFHxS-relevant hypothesis involving KEAP1–NRF2 signaling. Across clinical datasets, higher NQO1, an NRF2-associated gene, was linked to adverse clinicopathologic features; NQO1-high tumor cells showed elevated NRF2-activity signatures and computationally inferred increased MIF signaling toward macrophages. Because exposure information is unavailable, these observations indicate association and define a PFHxS-relevant vulnerability axis rather than PFHxS-driven tumor states. Docking/dynamics suggested PFHxS can bind the KEAP1 Kelch domain near the NRF2-binding site. In HepG2 cells, PFHxS modestly increased viability/DNA-synthesis readouts and enhanced NRF2 nuclear localization, NQO1 protein abundance, and MIF secretion; pharmacologic NRF2 inhibition partially attenuated NRF2/NQO1 readouts and reduced MIF secretion. Together, the data support the hypothesis that PFHxS may engage a KEAP1–NRF2-related vulnerability axis, accompanied by NRF2/NQO1 pathway readouts and increased MIF secretion, motivating exposure-characterized and genetic studies to establish causality.
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PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2015
·
IF 3.529
Chuanyang Su,Pu Zhang,Xiufang Song,Qiong Shi,Juanli Fu,Xiaomin Xia,Huiyuan Bai,Lihua Hu,Demei Xu,Erqun Song,Yang Song
Tetrachlorobenzoquinone (TCBQ), a metabolite of industrial herbicide pentachlorophenol, showed hepatotoxicity and genotoxicity through reactive oxygen species (ROS) mechanism in vivo and in vitro models. Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a cellular sensor of oxidative or electrophilic stress, which controls the expression of detoxifying enzymes and antioxidant proteins. Using the human hepatoma HepG2 cell line as an in vitro model, we demonstrated a significant induction of Nrf2 but not its negative regulator Kelch-like ECH-associated protein 1 (Keap1), following exposure to TCBQ. Also, our results clearly demonstrated the translocation of cytosolic Nrf2 into the nucleus. After translocation, Nrf2 subsequently binds to the antioxidant response element (ARE), up-regulated heme oxygenase-1 (HO-1), and NADH quinone oxidoreductase subunit 1 (NQO1), which may be considered as an antioxidative response to TCBQ-intoxication. The luciferase reporter assay confirmed the formation of the Nrf2-ARE complex. Furthermore, mechanism studies proposed that TCBQ promoted the formation of the Keap1 cross-linking dimer, a ubiquitination switch from Nrf2 to Keap1 but not the dissociation of the Keap1-Cullin3 (Cul3) complex.
研究领域:
毒理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Tang Honglin,Wu Chongzhi,Wang Wei,Cheng Xi,Dong Yong,Gao Zhiyuan,Chen Pengfei,Xie Xin,Huang Yong,Sun Lihe,Li Bowen,Li Da
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation (LPO), has emerged as a promising strategy for cancer therapy but remains limited by insufficient hydrogen peroxide (H₂O₂), restricted catalytic iron availability, and the extremely short lifetime of hydroxyl radicals (·OH) in the tumor microenvironment. Here, we report a self-assembled nano-prodrug designed to amplify oxidative stress through coordinated reactive oxygen species (ROS)-reactive nitrogen species (RNS) cascades. Transcriptomic analyses of melanoma cohorts revealed that the redox enzyme NAD(P)H: quinone oxidoreductase-1 (NQO1) is frequently upregulated and associated with oxidative stress and ferroptosis-related transcriptional programs, suggesting a potential redox vulnerability that can be therapeutically exploited. Guided by this observation, a glutathione-responsive nanoplatform (HFSAL) was constructed from a disulfide-bridged ferrocene–arginine scaffold (Fc-SS-Arg) with β-lapachone (β-lapa) co-loaded and hyaluronic acid coating for tumor-targeted delivery. Upon intracellular activation, β-lapa undergoes NQO1-mediated redox cycling to generate H₂O₂, which is further converted into ·OH through ferrocene-catalyzed Fenton reactions. Meanwhile, arginine-derived nitric oxide (NO) reacts with ROS intermediates to form highly reactive peroxynitrite (ONOO⁻), thereby amplifying oxidative damage and extending the effective range of redox stress. In addition, NO-mediated vascular remodeling alleviates tumor hypoxia and enhances intratumoral drug accumulation. Consequently, the HFSAL nano-prodrug effectively induces synergistic ferroptosis and apoptosis, leading to significant tumor growth inhibition and metastasis suppression in vivo with favorable biosafety. This work presents a redox-amplifying nano-prodrug strategy that exploits NQO1-associated metabolic vulnerability to enhance ferroptosis-based cancer therapy. Graphical
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高影响因子
International Journal of Pharmaceutics-X
·
2026
·
IF 6.4
Xu Luo,Ziqiong Yang,Jianqiu Chen,Mengqi Shen,Kun Wang,Qian Du
Colorectal cancer chemotherapy faces challenges with low intratumoral drug accumulation and off-target toxicity. Micellar liposome complex carriers are a promising anti-cancer platform due to their high encapsulation efficiency, responsive release, and multi-targeting capabilities. This study explores a novel tumor-targeted chemotherapy approach by encapsulating GSH/NQO1-responsive SN38 prodrug micelles into cholesterol-replacement multifunctional liposomes. Timosaponin AIII (TAIII), a steroid saponin with anticancer activity, substitutes cholesterol to stabilize liposomes, benefiting from its steroidal aglycone structure. Additionally, TAIII mimics PEGylation via its glucose moiety, enhancing tumor targeting via the overexpression of glucose transporter 1 (GLUT1) on cancer cells. Molecular docking studies with AutoDock revealed that GLUT1 residues stabilize TAIII in the binding pocket through hydrogen bonding, hydrophobic, and polar interactions, promoting its transmembrane transport. A specific amphiphilic SN38 prodrug, PEG-SS-SN38-QPA (PSSQ), was synthesized and self-assembled into micelles via a solvent injection-dialysis method for GSH/NQO1-responsive controlled drug release in the tumor microenvironment. PSSQ micelles were integrated into the hydrophilic cavity of TAIII-based liposomes (TLP, prepared by the thin-film hydration method) through passive encapsulation to form PSSQ@TLP. In vitro release study exhibiting GSH/NQO1-triggered release under simulated tumor microenvironment. In vitro cytotoxicity evaluation was performed using the MTT assay on HCT116, LOVO, CT26.WT cell lines. Following in vivo evaluations of biodistribution, anti-tumor efficacy, and biosafety in CT26.WT xenograft tumor-bearing mice, PSSQ@TLP demonstrated enhanced intratumoral accumulation, robust tumor suppression, and minimized systemic toxicity, underscoring its promise as a targeted therapeutic strategy for colorectal cancer.
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PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 5
·1103
·
IF 4.6
Bin Zhang,Xiaoyu Wei,Peiwen Du,Huangqun Luo,Lanfang Hu,Liping Guan,Guangying Chen
Polysaccharides are very promising molecules in the field of pharmacotherapy. Knowing this, the aim of this study was to extract, characterize, and evaluate the action of the polysaccharides in noni juice, using biological models of Type 2 diabetes mellitus processes. In this study, one polysaccharide named NJSPd−1 was separated from fermented noni fruit juice. The characterization assay showed that NJSPd−1 had a molecular weight ( Mw ) of 18,545 Da. NJSPd−1 consisted of galacturonic acid, galactose, rhamnose, and arabinose, with a molar ratio of 28.79:20.34:19.80:18.84 according to HPGPC analysis, and the glycosidic bond mainly included →4)- α -D-GalA p -(1→, 4)- β -D-Glc p -(1→, →2)- α -L-Rha p -(1→, and →3)- α -L-Ara f -(1→. The prevention of oxidative stress activities by NJSPd−1 was evaluated using high-glucose-induced oxidative stress in HepG2 cells. In vitro results showed that NJSPd−1 influenced the downregulation of the proteins and genes Nrf2, Keap1, HO-1, and NQO1 in HepG2 cells. These results suggest that NJSPd−1 exerted a protective effect against oxidative stress in HepG2 cells by activating the Nrf2/HO-1/NQO1 signaling pathway.
研究领域:
药理学
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生物化学
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PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 14
·6768
·
IF 13.3
Li He,Jiao-Jiao Ma,Yi-Qun Wu,Chen-Guang Wang,Tong Lan,Lu Su,Lin Zhu,Shi-Wen Huang,Kai Deng,Yong-Chang Wei
Background: Immunogenicity activation is vital for radioimmunotherapy, but the short-term oxidative damage caused by precise radiation planning limits this effect. Chemodynamic therapy (CDT) with prolonged generation of hydroxyl radical (•OH) can initiate immunogenicity in combination with X-rays, however, its performance is constrained by tumor insufficient H2O2. Methods: Here, we propose to construct β-lapachone-based nanoparticles (β-Lap/Fe NPs) which initiate cascade reactions to generate high levels •OH for an extended period in tumor following X-ray irradiation. Results: β-Lap/Fe NPs, constructed by co-encapsulation of β-Lap and Fe3O4 nanoparticles in reactive oxygen species (ROS) responsive C16-S-mPEG2000 micelles, remain stable under normal conditions but rapid decompose and release β-Lap and Fe2+ when exposed to high level ROS. Upon X-ray irradiation, the upregulation of ROS and NAD (P) H: quinone oxidoreductase-1 (NQO1) in tumor cells accurately triggers β-Lap/Fe NPs to persistently generate high levels H2O2 and •OH for 12 hours, ultimately causing strong immunogenic cell death effects. Moreover, β-Lap/Fe NPs with excellent T2-weighted magnetic resonance imaging provide imaging reference for guiding precise X-ray radiation and predicting •OH generation. β-Lap/Fe NPs mediated radio-chemodynamic-immunotherapy remarkably against primary tumor growth, and further shows effective suppression on untreated distant tumors via the abscopal effect. Conclusions: In a word, this work proposed the simple but powerful strategy for cancer radio-chemodynamic-immunotherapy that combines X-ray and CDT to remote locally and visually actuated long-time production of H2O2 and subsequently persistent generation of •OH for initiating strong antitumor immune responses.
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高影响因子
REDOX REPORT
·
2025
·
IF 7.4
Tianyi Wang,Jiale Huang,Jian Zhou,Mingjie Xia,Zheng Zhou,Qianqiu Li,Guanhua Xu,Zhanyang Qian,Zhiming Cui
Background: Spinal cord injury (SCI)-induced mitochondrial dysfunction in microglia exacerbates neuroinflammation and neurological deficits. Monoammonium glycyrrhizinate (MAG), a bioactive liquorice-derived compound, exhibits anti-inflammatory and antioxidant properties; however, its effects on microglial mitochondria remain unknown.Methods: Mice received a moderate contusion injury at the T10 spinal segment. Histopathology was assessed using Hematoxylin-Eosin, Nissl staining, and Luxol Fast Blue; locomotor recovery was evaluated via the Basso Mouse Scale, hindlimb flexion scoring, and gait footprint analysis. RNA-Seq and molecular docking identified KEAP1/NRF2 signaling. Verification employed qPCR, Western blot, and immunofluorescence. Mitochondrial function was gauged by JC-1 and MitoSOX.Results: In SCI mice, MAG attenuated neuroinflammation, reduced neuronal tissue loss and demyelination, enhanced neuronal survival, and improved functional recovery. Transcriptomic and molecular docking established that MAG directly activates NRF2, promoting dissociation from KEAP1, nuclear translocation, and induction of NQO1. Pathway enrichment analysis further indicated MAG modulation of mitochondrial regulatory processes. MAG treatment significantly restored mitochondrial function in BV2 cells, improving membrane potential and reducing oxidative stress. Critically, NRF2 inhibition with ML385 abolished MAG's protective effects on anti-inflammatory responses and antioxidant activity.Conclusion: This study identifies MAG as a novel activator of the KEAP1/NRF2/NQO1 axis, alleviating microglial mitochondrial dysfunction and neuroinflammation post-SCI. These findings provide mechanistic insights into MAG's neuroprotective actions and support its therapeutic potential.
研究领域:
神经科学
·
药理学
·
分子生物学
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炎症研究
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线粒体生物学
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DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-15
·
IF 3.8
Wang Yan,Wang Shasha,Ma Chenchen,Qi Weiwei,Lv Jing,Zhang Mengqi,Wang Shibo,Wang Rui,Lu Yangyang,Qiu Wensheng
Gastric cancer (GC) is the most common malignant tumor of the gastrointestinal tract and currently has a poor clinical outcome. Turmeric’s rhizome contains a polyphenolic component called curcumin (Cur), which has been demonstrated to inhibit a variety of tumor cells, such as pancreatic, colon, lung and gastric cancers. However, it remains to be elucidated how Cur functions in GC and what molecular processes underlie it. Here, Cur showed a stronger inhibitory effect on GC cells AGS and HGC27. In addition, Cur’s inhibition of GC cells growth was accompanied by increased ROS production, triggering of the Keap1-Nrf2 signaling pathway, and increased transcription of its downstream antioxidant genes HO-1, GCLM, and NQO1. However, when a ROS scavenger NAC was used, the inhibitory effect of Cur on GC cells was reversed. Nuclear factor erythroid 2-related factor 2 (Nrf2) is overexpressed or activated in cancers to shield cancer cells from oxidative damage by responding to oxidative stress (OS). Cur has been found to act as an activator of Nrf2. Notably, compared with Nrf2 knockdown and Cur alone, the combination of the two dramatically increased Cur-induced ROS overaccumulation and inhibition of GC cells proliferation, migration, and invasive abilities. Consistent with in vitro experiments, Cur combined with Nrf2 knockdown significantly inhibited tumor growth in nude mice transplanted with AGS cells. Therefore, we concluded that Nrf2 depletion enhanced Cur therapy effect in GC by inducing the excessive accumulation of ROS, indicating that this is a promising treatment strategy.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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PubMed
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 4
·548
·
IF 4.8
Huiming Xue,Zhen Feng,Chang Jin,Yue Zhang,Yongxing Ai,Jing Wang,Meizhu Zheng,Dongfang Shi
Objectives: Ischemic stroke is a severe neurological disorder with high morbidity, mortality, and disability rates, posing a substantial burden on patients, families, and healthcare systems. Soy isoflavone (SI), a naturally occurring phytoestrogen, has demonstrated promising neuroprotective effects. This study aimed to evaluate the anti-stroke efficacy of SI and elucidate its underlying mechanisms through integrated phytochemical profiling, network pharmacology, and both in vitro and in vivo experimental validation.Methods: Active constituents of SI were extracted via reflux and identified using liquid chromatography–mass spectrometry (LC-MS). Network pharmacology was employed to predict therapeutic targets and signaling pathways. The neuroprotective effects of SI were first assessed in PC12 cells subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) injury in vitro. For in vivo evaluation, transient cerebral ischemia–reperfusion injury was induced using the bilateral common carotid artery occlusion (BCCAO) model in adult male ICR rats (27.3 ± 1.8 g; 6–8 weeks old), obtained from the Shanghai Experimental Animal Center, Chinese Academy of Sciences. Forty-eight rats were randomly assigned into four groups (n= 12): sham, model (BCCAO), SI-treated (100 mg/kg, oral gavage for 5 days), and edaravone (EDA)-treated (10 mg/kg, i.p., positive control). All procedures were approved by the Institutional Animal Care and Use Committee of Changchun Normal University (Approval No. 2024003, 13 March 2024) and conducted in accordance with the NIH guidelines and ARRIVE 2.0 reporting standards.Results: In vitro, SI significantly enhanced PC12 cell viability from 57.23 ± 2.88% to 80.76 ± 4.43% following OGD/R. It also reduced intracellular Ca2+by 58.42%, lactate dehydrogenase (LDH) release by 37.67%, caspase-3 activity by 55.05%, and reactive oxygen species (ROS) levels by 74.13% (p< 0.05). A flow cytometry analysis revealed that OGD/R increased the apoptosis rate from 5.34% (control) to 30.85% (model group), which was significantly attenuated by SI treatment, especially in the 560 µg/mL group (20.00%), followed by the 140 and 280 µg/mL groups. In vivo, SI improved neurological scores from 8.3 ± 1.09 to 6.8 ± 1.68, reduced cerebral infarction volume by 18.49%, and alleviated brain edema by 10.42% (p< 0.05). SI also decreased malondialdehyde (MDA) and LDH levels by 31.15% and 39.46%, respectively, while increasing the activity of antioxidant enzymes: superoxide dismutase (SOD) by 11.70%, catalase (CAT) by 26.09%, and glutathione peroxidase (GSH-px) by 27.55% (p< 0.01). Scratch assay results showed that SI restored the impaired migratory ability of the OGD/R-treated PC12 cells, further supporting its role in cellular repair. A Western blot analysis demonstrated the upregulation of nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1) and the downregulation of Kelch-like, ECH-associated protein 1 (Keap1) in the cerebral ischemia–reperfusion model.Conclusions: These findings indicate that soy isoflavone confers significant neuroprotective effects against cerebral ischemia–reperfusion injury by enhancing endogenous antioxidant defense mechanisms, reducing oxidative stress, inhibiting apoptosis, and promoting cell migration. The protective effects are likely mediated through the activation of the Nrf2/Keap1 signaling pathway, supporting the therapeutic potential of SI in ischemic stroke treatment.
研究领域:
药理学
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神经科学
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分子生物学
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PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Zixu Wang,Lujuan Xing,Jingyu Wang,Jiaming Cai,Yuejing Hao,Ye Tao,Wangang Zhang
Alcoholic fatty liver disease (AFLD) is considered as an initial stage in the development of alcoholic liver disease. The benefit of porcine liver hydrolysates (PLH) and porcine liver peptide (NTLPHPTAP) on AFLD was demonstrated in vitro HepG-2 cell model as well as in vivo C57BL/6J mice model. After PLH and NTLPHPTAP treatment, the reactive oxygen species (ROS) level, triglyceride (TG), and liver injury markers, including aspartate transaminase (AST) and alanine transaminase (ALT) were ameliorated. The result of transcriptomics reminded that the main functional pathways of PLH and NTLPHPTAP were enriched in oxidative phosphorylation and fatty acid metabolism. Further validation of pathway proteins found that NTLPHPTAP regulated oxidative stress levels and mitochondrial function by increasing NQO1 expression. Metabolism of fatty acid β-oxidation in mitochondria was increased via PLH and NTLPHPTAP treatment by ACAA1 regulation, which attenuated intracellular lipid deposition. In conclusion, PLH and NTLPHPTAP may be bioactive compounds for the application of AFLD treatment or alleviation.
研究领域:
肝脏病学
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分子生物学
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营养生物化学
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药理学
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代谢组学
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高影响因子
危险品化学品经营许可证（带存储）